Chemokine receptor binding heterocyclic compounds

ABSTRACT

This invention relates to a novel class of heterocyclic compounds that bind chemokine receptors, inhibiting the binding of their natural ligands thereby. These compounds result in protective effects against infection by HIV through binding to chemokine receptors, including CXCR4 and CCR5, thus inhibiting the subsequent binding by these chemokines. The present invention provides a compound of Formula I  
                 
 
     wherein, W is a nitrogen atom and Y is absent or, W is a carbon atom and Y=H;  
     R 1  to R 7  may be the same or different and are independently selected from hydrogen or straight, branched or cyclic C 1-6  alkyl;  
     R 8  is a substituted heterocyclic group or a substituted aromatic group  
     Ar is an aromatic or heteroaromatic ring each optionally substituted at single or multiple, non-linking positions with electron-donating or withdrawing groups;  
     n and n′ are independently, 0-2;  
     X is a group of the formula:  
                 
 
     Wherein, Ring A is an optionally substituted, saturated or unsaturated 5 or 6-membered ring, and P is an optionally substituted carbon atom, an optionally substituted nitrogen atom, sulfur or oxygen atom. Ring B is an optionally substituted 5 to 7-membered ring. Ring A and Ring B in the above formula can be connected to the group W from any position via the group V,  
     wherein V is a chemical bond, a (CH 2 ) n″  group (where n″=0-2) or a C═O group. Z is, (1) a hydrogen atom, (2) an optionally substituted C 1-6  alkyl group, (3) a C 0-6  alkyl group substituted with an optionally substituted aromatic or heterocyclic group, (4) an optionally substituted C 0-6  alkylamino or C 3-7  cycloalkylamino group, (5) an optionally substituted carbonyl group or sulfonyl. These compounds further include any pharmaceutically acceptable acid addition salts and metal complexes thereof and any stereoisomeric forms and mixtures of stereoisomeric forms thereof.

TECHNICAL FIELD

[0001] This invention generally relates to novel compounds,pharmaceutical compositions and their use. This invention morespecifically relates to novel heterocyclic compounds that bind tochemokine receptors, including CXCR4 and CCR5, and demonstratesprotective effects against infection of target cells by a humanimmunodeficiency virus (HIV).

BACKGROUND OF THE INVENTION

[0002] Approximately 40 human chemokines have been described, thatfunction, at least in part, by modulating a complex and overlapping setof biological activities important for the movement of lymphoid cellsand extravasation and tissue infiltration of leukocytes in response toinciting agents (See, for example: P. Ponath, Exp. Opin. Invest. Drugs,7:1-18, 1998). These chemotactic cytokines, or chemokines, constitute afamily of proteins, approximately 8-10 kDa in size. Chemokines appear toshare a common structural motif, that consists of 4 conserved cysteinesinvolved in maintaining tertiary structure. There are two majorsubfamilies of chemokines: the “CC” or β-chemokines and the “CXC” orα-chemokines. The receptors of these chemokines are classified basedupon the chemokine that constitutes the receptor's natural ligand.Receptors of the β-chemokines are designated “CCR”; while those of theα-chemokines are designated “CXCR”.

[0003] Chemokines are considered to be principal mediators in theinitiation and maintenance of inflammation. More specifically,chemokines have been found to play an important role in the regulationof endothelial cell function, including proliferation, migration anddifferentiation during angiogenesis and re-endothelialization afterinjury (Gupta et al., J. Biolog. Chem., 7:4282-4287, 1998). Two specificchemokines have been implicated in the etiology of infection by humanimmunodeficiency virus (HIV).

[0004] In most instances, HIV initially binds via its gp120 envelopeprotein to the CD4 receptor of the target cell. A conformational changeappears to take place in the gp120 which results in its subsequentbinding to a chemokine receptor, such as CCR-5 (Wyatt et al., Science,280:1884-1888 (1998)). HIV-1 isolates arising subsequently in theinfection bind to the CXCR-4 chemokine receptor. In view of the factthat the feline immunodeficiency virus, another related retrovirus,binds to a chemokine receptor without needing to bind first to the CD4receptor, suggests that chemokine receptors may be the primordialobligate receptors for immunodeficiency retroviruses.

[0005] Following the initial binding by HIV to CD4, virus-cell fusionresults, which is mediated by members of the chemokine receptor family,with different members serving as fusion cofactors for macrophage-tropic(M-tropic) and T cell line-tropic (T-tropic) isolates of HIV-1 (Carrollet al., Science, 276: 273-276 1997). During the course of infectionwithin a patient, it appears that a majority of HIV particles shift fromthe M-tropic to the more aggressive T-tropic viral phenotype (Miedema etal., Immune. Rev., 140:35 (1994)) Curiously, the M-tropic viralphenotype correlates with the virus's ability to enter the cellfollowing binding of the CCR-5 receptor, while the T-tropic viralphenotype correlates with viral entry into the cell following bindingand membrane fusion with the CXCR-4 receptor. Clinically observationssuggest that patients who possess genetic mutations in the CCR-5 orCXCR-4 appear resistant or less susceptible to HIV infection.

[0006] However, the binding of chemokine receptors to their naturalligands appears to serve a more evolutionary and central role than onlyas mediators of HIV infection. The chemokine receptor, CXCR-4 has beenfound to be essential for the vascularization of the gastrointestinaltract (Tachibana et al., Nature, 393:591-594 (1998)) as well ashaematopoiesis and cerebellar development (Zou et al., Nature,393:591-594 (1998)). Interference with any of these important functionsserved by the binding of pre-B-cell growth-stimulating factor/stromalderived factor (PBSF/SDF-1) to the CXCR-4 chemokine receptor results inlethal deficiencies in vascular development, haematopoiesis andcardiogenesis. Similarly, fetal cerebellar development appears to relyupon the effective functioning of CXCR-4 in neuronal cell migration andpatterning in the central nervous system. This G-protein-coupledchemokine receptor appears to play a critical role in ensuring thenecessary patterns of migration of granule cells in the cerebellaranlage.

[0007] In attempting to better understand the relationship betweenchemokines and their receptors, recent experiments to block the bindingof HIV to the CXCR-4 chemokine receptor were carried out through the useof monoclonal antibodies or small molecules that appear to suggest auseful therapeutic strategy (Schols et al., J. Exp. Med.186:1383-1388(1997); Schols et al., Antiviral Research 35:147-156(1997)). Small molecules, such as bicyclams, appear to specificallyinterfere with the CXCR-4 binding and not CCR-5 binding (Donzella etal., Nature Medicine, 4:72-77 (1998)). These experiments demonstratedinterference with HIV entry and membrane fusion into the target cell invitro. Additional experiments monitoring the calcium flux or Ca²⁺mobilization assay demonstrated that a bicyclam also functioned as anantagonist to signal transduction resulting from the binding of stromalderived factor or SDF-1α, the natural chemokine to CXCR-4. SDF-1 hasbeen shown to be essential for CXCR-4 dependent migration of human stemcell function in non-obese diabetic (NOD) severe combinedimmunodeficient (SCID) mice (Peled et al., Science 283: 845-848 (1998)).The role of CXCR-4 appears critical for migration to SDF-1 andlocalization of stem cells in bone marrow.

[0008] U.S. Pat. No. 5,583,131, U.S. Pat. No. 5,698,546 and U.S. Pat.No. 5,817,807, which are herein incorporated in their entirety byreference, disclose cyclic compounds that are active against HIV-1 andHIV-2 in in vitro tests. It was subsequently discovered and furtherdisclosed in copending application U.S. Ser. No. 09/111,895 that thesecompounds exhibit anti-HIV activity by binding to the chemokine receptorCXCR4 expressed on the surface of certain cells of the immune system.This competitive binding thereby protects these target cells frominfection by HIV which utilize the CXCR-4 receptor for entry. Inaddition, these compounds antagonize the binding, signaling andchemotactic effects of the natural CXC-chemokine for CXCR-4, stromalcell-derived factor 1α (SDF-1).

[0009] Additionally we have shown that these cyclic polyamine antiviralagents described in the above-mentioned patents have the effect ofenhancing production of white blood cells as well as exhibitingantiviral properties. Thus, these agents are useful for controlling theside-effects of chemotherapy, enhancing the success of bone marrowtransplantation, enhancing wound healing and burn treatment, as well ascombating bacterial infections in leukemia.

[0010] We further disclosed that these novel compounds demonstrateprotective effects against HIV infection of target cells by binding invitro to the CC-5 receptor (CCR-5).

[0011] Herein, we disclose novel compounds that exhibit protectiveeffects against HIV infection of target cells by binding to chemokinereceptors, including CXCR4 and CCR5, in a similar manner to thepreviously disclosed macrocyclic compounds. (see Table 1 for comparativeexamples).

SUMMARY OF THE INVENTION

[0012] The present invention provides novel compounds that bindchemokine receptors and interfere with the binding of the natural ligandthereto. The compounds of the present invention are useful as agentsdemonstrating protective effects on target cells from HIV infection.Other embodiments of the present invention are compounds that act asantagonists or agonists of chemokine receptors, which are useful asagents capable of reconstituting the immune system by increasing thelevel of CD4⁺ cells; as antagonist agents of apoptosis in immune cells,such as CD8⁺ cells, and neuronal cells; as antagonist agents ofmigration of human bone marrow B lineage cells to stromal-derived factor1, as well as other biological activities related to the ability ofthese compounds to inhibit the binding of chemokines to their receptors.Accordingly, the present invention provides a compound of Formula I

[0013] wherein, W is a nitrogen atom and Y is absent or, W is a carbonatom and Y=H;

[0014] R¹ to R⁷ may be the same or different and are independentlyselected from hydrogen or straight, branched or cyclic C₁₋₆ alkyl;

[0015] R⁸ is a substituted heterocyclic group or a substituted aromaticgroup

[0016] Ar is an aromatic or heteroaromatic ring each optionallysubstituted at single or multiple, non-linking positions withelectron-donating or withdrawing groups;

[0017] n and n′ are independently, 0-2;

[0018] X is a group of the formula:

[0019] Wherein, Ring A is an optionally substituted, saturated orunsaturated 5 or 6-membered ring, and P is an optionally substitutedcarbon atom, an optionally substituted nitrogen atom, sulfur or oxygenatom. Ring B is an optionally substituted 5 to 7-membered ring. Ring Aand Ring B in the above formula can be connected to the group W from anyposition via the group V, wherein V is a chemical bond, a (CH₂)_(n″)group (where n″=0-2) or a C═O group. Z is, (1) a hydrogen atom, (2) anoptionally substituted C₁₋₆ alkyl group, (3) a C₀₋₆ alkyl groupsubstituted with an optionally substituted aromatic or heterocyclicgroup, (4) an optionally substituted C₀₋₆ alkylamino or C₃₋₇cycloalkylamino group, (5) an optionally substituted carbonyl group orsulfonyl.

[0020] In the above Formula I, examples of the optionally substituted 5or 6-membered ring A are benzene, pyridine, pyrimidine, pyrazine,pyridazine, triazine, piperidine, piperazine, imidazole, pyrazole,triazole, oxazole, thiazole. Six-membered rings are preferred for ringA, particularly benzene, pyridine and piperidine.

[0021] The invention also provides a compound of Formula I

[0022] In which, W, Y, n, n′, Ar, R¹-R⁸ are defined as above,

[0023] X and Z are independently selected from H, optionally substitutedC₁₋₆ alkyl or C₀₋₆ alkaryl or C₀-6 alkylheterocyclyl groups. The X and Zgroups may also bind each other to form an optionally substituted 5- to7-membered cyclic amine group such as tetrahydropyrrole, pyrrolidine,piperazine, homopiperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole etc., or an optionally substituted pyran, thiopyranor cycloalkyl ring or the groups X and Z optionally fused to the groupAr.

[0024] The optional substituents are defined herein infra.

[0025] One preferred embodiment of the present invention is apharmaceutical composition comprising a therapeutically effective amountof the compound according to Formula I. Another preferred embodiment ofthis invention is a method of treating a disease of the human body orthe bodies of other mammals comprising the administration of apharmaceutical composition comprising a therapeutically effective amountof the compound according to Formula I. A still further embodiment ofthe present invention provides a method for blocking or interfering withthe binding by a chemokine receptor with its natural ligand, comprisingthe contacting of said chemokine receptor with an effective amount ofthe compound according to Formula I.

[0026] This invention may also provide for the use of a compound ofFormula I in the manufacture of a medicament for the treatment of adisease in which blocking or interfering with binding of a chemokinereceptor with its natural ligand is advantageous, comprising formulatinga composition comprising a therapeutically effective amount of thecompound of Formula I. It is further contemplated that this invention isalso useful for providing a method of protecting target cells possessingchemokine receptors, the binding to which by a pathogenic agent resultsin disease or pathology, comprising administering to a mammalian subjecta pharmaceutical composition comprising a therapeutically effectiveamount of the compound according to Formula I.

[0027] The invention also includes what may be termed as “pro-drug”,that is, protected forms of the compounds, which release the compoundafter administration to a patient. For example, the compound may carry aprotective groups which is split off by hydrolysis in body fluids e.g.in the bloodstream, thus releasing active compound or is oxidized orreduced in body fluids to release the compound. A discussion ofpro-drugs may be found in “Smith and Williams' Introduction to thePrinciples of Drug Design”, H. J. Smith, Wright, Second Edition, London1988.

[0028] Acid addition salts, which are pharmaceutically acceptable suchas salt with inorganic base, a salt with organic base, a salt withinorganic acid, a salt with organic acid, a salt with basic or acidicamino acid, etc. Examples of the salt with the inorganic base include asalt with alkali metal (e.g. sodium, potassium, etc.), alkaline earthmetal (e.g. calcium, magnesium, etc.), aluminum, ammonium, etc. Examplesof the salt with the organic base include a salt with trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine etc.Examples of the salt with the inorganic acid include a salt withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, etc. Examples of the salt with the organic acid includea salt with formic acid, oxalic acid, acetic acid, tartaric acid,methanesulfonic acid, benzenesulfonic acid, malic acid, methanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Examples of thesalt with the basic amino acid include a salt with arginine, lysine,ornithine, etc. Examples of the salt with the acidic amino acid includea salt with aspartic acid, glutamic acid, etc. Non-toxic in the presenttense has to be considered with reference to the prognosis for theinfected patient without treatment.

[0029] Citation of the above documents is not intended as an admissionthat any of the foregoing is pertinent prior art. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents. Further, all documents referred to throughout thisapplication are hereby incorporated in their entirety by referenceherein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030]FIG. 1, shows structural formulas of compounds of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention is directed to compounds of Formula I whichcan act as agents that modulate chemokine receptor activity. Suchchemokine receptors includes but are not limited to CCR-1, CCR-2, CCR-3,CCR-4, CCR-5, CXCR-3, and CXCR-4.

[0032] In one embodiment, the present invention provides novel compoundsof Formula I that demonstrates protective effects on target cells fromHIV infection in a manner as to bind specifically to the chemokinereceptor, which effect the binding of a natural ligand or chemokine tothe receptor such as CCR-5 and/or CXCR-4 of a target cell.

[0033] In another embodiment, compounds of Formula I may be useful asagents which affect chemokine receptors, such as CCR-1, CCR-2, CCR-3,CCR-4, CCR-5, CXCR-3, CXCR-4 where such chemokine receptors have beencorrelated as being important mediators of many human inflammatory aswell as immunoregulatory diseases.

[0034] Other diseases that are also implicated with chemokine asmediators include angiogenesis, and tumorigenesis such as brain, andbreast tumors. Thus, a compound that modulates the activity of suchchemokine receptors would be useful for the treatment or prevention ofsuch diseases.

[0035] The term “modulators” as used herein is intended to encompassantagonist, agonist, partial antagonist, and or partial agonist,inhibitors, and activators. In the preferred embodiment of the presentinvention, compounds of Formula I demonstrates protective effect againstHIV infection by inhibiting the binding of HIV to a chemokine receptorsuch as CCR-5 and/or CXCR-4, of a target cell, which comprisescontacting the target cell with an amount of the compound which iseffective at inhibiting the binding of the virus to the chemokinereceptor.

[0036] Compounds that inhibits chemokine receptor activity and functionmay be used for the treatment of diseases that are associated withinflammation, including but are not limited to, inflammatory or allergicdiseases such as asthma, allergic rhinitis, hypersensitivity lungdiseases, hypersensitivity pneumonitis, eosinophilic pneumonias,delayed-type hypersensitivity, interstitial lung disease (ILD) (e.g.,idiopathic pulmonary fibrosis, or ILD associated with rheumatoidarthritis, systemic lupus erythematosus, ankylosing spondylitis,systemic sclerosis, Sjogren's syndrome, polymyositis ordermatomyositis); systemic anaphylaxis or hypersensitivity responses,drug allergies, insect sting allergies; autoimmune diseases, such asrheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus,myastenia gravis, juvenile onset diabetes; glomerulonephritis,autoimmune throiditis, graft rejection, including allograft rejection orgraft-versus-host disease; inflammatory bowel diseases, such as Crohn'sdisease and ulcerative colitis; spondyloarthropathies; scleroderma;psoriasis (including T-cell mediated psoriasis) and inflammatorydermatoses such as dermatitis, eczema, atopic dermatitis, allergiccontact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous,and hypersensitivity vasculitis); eosinphilic myotis, eosiniphilicfasciitis; and cancers.

[0037] Whereas compounds that activate or promote chemokine receptorfunction may be used for the treatment of diseases that are associatedwith immunosuppression such as individuals undergoing chemotherapy,radiation therapy, enhanced wound healing and bum treatment, therapy forautoimmune disease or other drug therapy (e.g., corticosteroid therapy)or combination of conventional drugs used in the treatment of autoimmunediseases and graft/transplantation rejection, which causesimmunosuppression; immunosuppresion due to congenital deficiency inreceptor function or other causes; and infectious diseases, such asparasitic diseases, including but not limited to helminth infections,such as nematodes (round worms); Trichuriasis, Enterobiasis, Ascariasis,Hookworm, Strongyloidiasis, Trichinosis, filariasis; trematodes;visceral worms, visceral larva migtrans (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki spp., Phocanema ssp.), cutaneous larvamigrans (Ancylostona braziliense, Ancylostoma caninum); themalaria-causing protozoan Plasmodium vivax, Human cytomegalovirus,Herpesvirus saimiri, and Kaposi's sarcoma herpesvirus, also known ashuman herpesvirus 8, and poxvirus Moluscum contagiosum.

[0038] It will be understood that that compounds of Formula I may beused in combination with any other pharmaceutical composition where suchcombined therapy may be useful to modulate chemokine receptor activityand thereby prevent and treat inflammatory and immunoregulatorydiseases.

[0039] It is also contemplated that the present invention may be used incombinations with one or more agents useful in the prevention ortreatment of HIV. Examples of such agents include:

[0040] (1) nucleotide reverse transcriptase inhibitor such aszidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine,adefovir, adefovir dipivoxil, fozivudine todoxil, etc.;

[0041] (2) non-nucleotide reverse transcriptase inhibitor (including anagent having anti-oxidation activity such as immunocal, oltipraz, etc.)such as nevirapine, delavirdine, efavirenz, loviride, immunocal,oltipraz, etc.; and

[0042] (3) protease inhibitors such as saquinavir, ritonavir, indinavir,nelfinavir, amprenavir, palinavir, lasinavir, etc.

[0043] It will be understood that the scope of combinations of compoundsof Formula 1 of this invention with HIV agents is not limited to (1),(2), and or (3), but includes in principle any combination with anypharmaceutical composition useful for the treatment of HIV. Further, insuch combinations the compounds of the present invention and other HIVagents may be administered separately or in conjunction. In addition,the administration of one element may be prior to, concurrent to, orsubsequent to the administration of other agent(s).

[0044] The compounds of Formula I in the present invention may beadministered by oral, parenteral (e.g., intramuscular, intraperitoneal,intravenous, intracisternal injection or infusion, subcatenousinjection, or implant), by inhalation spray, nasal, vaginal, rectal,sublingual, or topical routes of administration and may be formulated,alone or together, in suitable dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles appropriate for each route of administration.

[0045] The compounds of Formula I are all active and used to treatanimals, including mice, rats, horses, cattle, sheep, dogs, casts, andmonkey. The compounds of the invention are also effective for use inhumans.

[0046] The compounds of Formula I of the present invention may formhydrates or solvates. Compounds of Formula I of the present inventioncan exist as any stereoisomeric forms and mixtures of stereoisomericforms thereof where it is possible to isolate individual isomers withknown separation and purification method, if desired. When the compoundof the Formula I of the present invention is racemate, it can beseparated into (S)-compound and (R)-compound with usual opticalresolution and individual optical isomers and a mixture thereof areincluded in the scope of the of the present invention.

[0047] This invention also relates to a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier or diluent and aneffective amount of compound of Formula I. A compound of Formula I maybe administered alone or as an admixture with a pharmaceuticallyacceptable carrier (e.g. solid formulations such as tablets, capsules,granules, powders, etc.; liquid formulations such as syrups, injections,etc.) may be orally or non-orally administered. Examples of non-oralformulations include injection, drops, suppositories, pessaryies.

[0048] In the treatment or prevention of conditions which requirechemokine receptor modulation an appropriate dosage level will generallybe about 0.01 to 500 mg per kg patient body weight per day which can beadministered in singe or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day. It will be understood thatthe specific dose level and frequency of dosage for any particularpatient may be varied and will depend upon a variety of factorsincluding the activity of the specific compound used, the metabolicstability and length of action of that compound, the age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the particular condition,and the patient undergoing therapy.

[0049] The present invention further provides novel compounds that bindchemokine receptors and interfer with the binding of the natural ligandthereto. The compounds of the present invention are useful as agentsdemonstrating protective effects on target cells from HIV infection. Thecompounds of the present invention are also useful as antagonists oragonists of chemokine receptors, which serve as agents capable ofreconstituting the immune system by increasing the level of CD4⁺ cells;as antagonist agents of apoptosis in immune cells, such as CD8⁺ cells,and neuronal cells; as antagonist agents of migration of human bonemarrow B lineage cells to stromal-derived factor 1, as well as otherbiological activities related to the ability of these compounds toinhibit the binding of chemokines to their receptors.

[0050] Accordingly, the present invention provides a compound of FormulaI

[0051] wherein, W is a nitrogen atom and Y is absent or, W is a carbonatom and Y=H;

[0052] R¹ to R⁷ may be the same or different and are independentlyselected from hydrogen or straight, branched or cyclic C₁₋₆ alkyl;

[0053] R⁸ is a substituted heterocyclic group or a substituted aromaticgroup

[0054] Ar is an aromatic or heteroaromatic ring each optionallysubstituted at single or multiple, non-linking positions withelectron-donating or withdrawing groups;

[0055] n and n′ are independently, 0-2;

[0056] X is a group of the formula:

[0057] Wherein, Ring A is an optionally substituted, saturated orunsaturated 5 or 6-membered ring, and P is an optionally substitutedcarbon atom, an optionally substituted nitrogen atom, sulfur or oxygenatom. Ring B is an optionally substituted 5 to 7-membered ring. Ring Aand Ring B in the above formula can be connected to the group W from anyposition via the group V, wherein V is a chemical bond, a (CH₂)_(n″)group (where n″=0-2) or a C═O group. Z is, (1) a hydrogen atom, (2) anoptionally substituted C₁₋₆ alkyl group, (3) a C₀₋₆ alkyl groupsubstituted with an optionally substituted aromatic or heterocyclicgroup, (4) an optionally substituted C₀₋₆ alkylamino or C₃₋₇cycloalkylamino group, (5) an optionally substituted carbonyl group orsulfonyl.

[0058] In the above Formula I, examples of the optionally substituted 5or 6-membered ring A are benzene, pyridine, pyrimidine, pyrazine,pyridazine, triazine, piperidine, piperazine, imidazole, pyrazole,triazole, oxazole, thiazole. Six-membered rings are preferred for ringA, particularly benzene, pyridine and piperidine.

[0059] Examples of the optionally substituted ring B are benzene, 5 to7-membered cycloalkyl rings (e.g. cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cycloheptenyl), furan, dihydrofuran,tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene(thiolane), pyran, dihydropyran, tetrahydropyran, thiapyran,dihydrothiapyran, tetrahydrothiapyran (pentamethylene sulfide), oxepine,thiepin (and their corresponding saturated heterocycloalkanes) inaddition to those listed above for ring A. Six-membered rings are alsopreferred for ring B, with the preferred combination of the rings A andB being, dihydronaphthalene, tetrahydronaphthalene, dihydroquinoline andtetrahydroquinoline.

[0060] In the above examples, the “optional substituents” in Rings A andB may be halogen, nitro, cyano, carboxylic acid, an optionallysubstituted alkyl, alkenyl or cycloalkyl groups, an optionallysubstituted hydroxyl group, an optionally substituted thiol group, anoptionally substituted amino or acyl group, an optionally substitutedcarboxylate, carboxamide or sulfonamide group, an optionally substitutedaromatic or heterocyclic group.

[0061] Examples of halogen include fluorine, chlorine, bromine, iodine,etc., with fluorine and chlorine preferred.

[0062] Examples of the optionally substituted alkyl include C₁₋₁₀ alkyl,including methyl, ethyl propyl etc., examples of the optionallysubstituted alkenyl groups include, C₂₋₁₀ alkenyl such as allyl, crotyl,2-pentenyl, 3-hexenyl, etc., and examples of the optionally substitutedcycloalkyl groups include C₃₋₁₀ cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. In these cases,C₁₋₆ alkyl, alkenyl and cycloalkyl are preferred. The optionalsubstituent may also be an optionally substituted aralkyl (e.g.phenylC₁₋₄ alkyl) or heteroalkyl for example, phenylmethyl (benzyl),phenethyl, pyridinylmethy, pyridinylethyl etc. The heterocyclic groupmay be a 5 or 6 membered ring containing 1-4 heteroatoms.

[0063] Examples of the optionally substituted hydroxyl and thiol groupsinclude an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl) such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl etc., preferably (C₁₋₆)alkyl; an optionallysubstituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc. such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); an optionallysubstituted aralkyl (e.g. phenyl-C₁₋₄ alkyl, e.g. benzyl, phenethyl,etc.). Where there are two adjacent hydroxyl or thiol substituents, theheteroatoms may be connected via an alkyl group such as O(CH₂)_(n)O andS(CH₂)_(n)S (where n=1-5). Examples include methylenedioxy,ethylenedioxy etc. Oxides of thio-ether groups such as sulfoxides andsulfones are also encompassed.

[0064] Further examples of the optionally substituted hydroxyl groupinclude an optionally substituted C₂₋₄ alkanoyl (e.g. acetyl, propionyl,butyryl, isobutyryl, etc.), C₁₋₄ alkylsufonyl (e.g. methanesulfonyl,ethanesulfonyl, etc.) and an optionally substituted aromatic andheterocyclic carbonyl group including benzoyl, pyridinecarbonyl etc.

[0065] The substituents on the optionally substituted amino group maybind to each other to form a cyclic amino group (e.g. 5- to 6-memberedcyclic amino, etc. such as tetrahydropyrrole, piperazine, piperidine,pyrrolidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.). Saidcyclic amino group may have a substituent, and examples of thesubstituents include halogen (e.g. fluorine, chlorine, bromine, iodine,etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxylgroup, an optionally halogenated C₁₋₄ alkyl (e.g. trifluoromethyl,methyl, ethyl, etc.), an optionally halogenated C₁₋₄ alkoxy (e.g.methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C₂₋₄ alkanoyl(e.g. acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g.methanesulfonyl, ethanesulfonyl, etc.) the number of preferredsubstituents are 1 to 3.

[0066] The amino group may also be substituted once or twice (to form asecondary or tertiary amine) with a group such as an optionallysubstituted alkyl group including C₁₋₁₀ alkyl (e.g. methyl, ethyl propyletc.); an optionally substituted alkenyl group such as allyl, crotyl,2-pentenyl, 3-hexenyl, etc., or an optionally substituted cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc. In these cases, C₁₋₆ alkyl, alkenyl and cycloalkyl arepreferred. The amine group may also be optionally substituted with anaromatic or heterocyclic group, aralkyl (e.g. phenylC₁₋₄ alkyl) orheteroalkyl for example, phenyl, pyridine, phenylmethyl (benzyl),phenethyl, pyridinylmethyl, pyridinylethyl etc. The heterocyclic groupmay be a 5 or 6 membered ring containing 1-4 heteroatoms. The optionalsubstituents of the “optionally substituted amino groups are the same asdefined above for the “optionally substituted cyclic amino group.”

[0067] The amino group may be substituted with an optionally substitutedC₂₋₄ alkanoyl e.g. acetyl, propionyl, butyryl, isobutyryl etc., or aC₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.) or acarbonyl or sulfonyl substituted aromatic or heterocyclic ring, e.g.benzenesulfonyl, benzoyl, pyridinesulfonyl, pyridinecarbonyl etc. Theheterocycles are as defined above.

[0068] Examples of the optionally substituted acyl group as thesubstituents on the rings A and B include a carbonyl group or a sulfonylgroup binding to hydrogen; an optionally substituted alkyl (e.g. C₁₋₁₀alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,octyl, nonyl, decyl, etc., preferably lower (C₁₋₆)alkyl, etc.; anoptionally substituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc., such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); anoptionally substituted alkenyl (e.g. C₂₋₁₀ alkenyl such as allyl,crotyl, 2-pentenyl, etc., preferably lower (C₂₋₆)alkenyl, etc.); anoptionally substituted cycloalkenyl (e.g. C₃₋₇ cycloalkenyl, etc., suchas 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,2-cyclohexenylmethyl, etc.) an optionally substituted 5- to 6-memberedmonocyclic aromatic group (e.g. phenyl, pyridyl, etc.).

[0069] Examples of the optionally substituted carboxylate group (estergroups) include an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., preferably lower (C₁₋₆)alkyl, etc.); an optionallysubstituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc. such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.); an optionallysubstituted alkenyl (e.g. C₂₋₁₀ alkenyl such as allyl, crotyl,2-pentenyl, 3-hexenyl, etc., preferably lower (C₂₋₆)alkenyl, etc.); anoptionally substituted cycloalkenyl (e.g. C₃₋₇ cycloalkenyl, etc., suchas 2-cyclohexenylmethyl, etc.); an optionally substituted aryl (e.g.phenyl, naphthyl, etc.) and C₁₋₄ aryl for example, benzyl, phenethyletc. Groups such as methoxymethyl, methoxyethyl etc., are alsoencompassed.

[0070] Examples of the optionally substituted carboxamide andsulfonamide groups are identical in terms of the amine definition as the“optionally substituted amino group” defined above.

[0071] Examples of the optionally substituted aromatic or heterocyclicgroups as substituents for Rings A and B are phenyl, naphthyl, or a 5-or 6-membered heterocyclic ring containing 1-4 heteroatoms. The optionalsubstituents are essentially identical to those listed above for Rings Aand B.

[0072] In the above examples the number of substituents on Rings A and Bmay be 1-4, preferably 1-2. The substituents on the optionallysubstituted groups are the same as the optionally substituted groupsdescribed above. Preferred substituents are halogen (fluorine, chlorineetc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxylgroup, carboxylate group, sulfonate group, sulfonamide group,carboxamide group, an optionally halogenated C₁₋₄ alkoxy (e.g.trifluoromethoxy, etc.), C₂₋₄ alkanoyl (e.g. acetyl, propionyl, etc.) oraroyl, a C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl,etc.), an optionally substituted aryl or heterocyclic group. The numberof substituents on the said groups are preferably 1 to 3.

[0073] In the above Formula I, Z may be (2) an optionally substitutedC₁₋₆ alkyl group where the optional substituents are identical to thosedescribed for Rings A and B above.

[0074] In the above Formula I, Z may be (3) a C₀₋₆ alkyl groupoptionally substituted with an optionally substituted fused or unfused,aromatic or heterocyclic group. Examples of the optionally substitutedaromatic groups include benzene and naphthalene, or dihydronaphthaleneand tetrahydronaphthalene. Examples of optionally substitutedheterocyclic groups include 5 to 6-membered saturated, partiallysaturated, or aromatic heterocyclic rings containing I to 4 heteroatomsselected from nitrogen, oxygen and sulfur. The heterocycles may bepyridine, quinoline, isoquinoline, imidazole, benzimidazole,azabenzimidazole, benzotriazole, furan, benzofuran, thiazole,benzothiazole, oxazole, benzoxazole, pyrrole, indole, indoline,indazole, pyrrolidine, pyrrolidone, pyrroline, piperidine, piperazine,tetrahydroquinoline, tetrahydroisoquinoline, pyrazole, thiophene,isoxazole, isothiazole, triazole, tetrazole, oxadiazole, thiadiazole,morpholine, thiamorpholine, pyrazolidine, imidazolidine, imidazoline,tetrahydropyran, dihydropyran, benzopyran, dioxane, dithiane,tetrahydrofuran, tetrahydrothiophene, dihydrofuran, dihydrothiopheneetc. Oxides of the nitrogen and sulfur containing heterocycles are alsoincluded in the present invention. The optionally substituted aromaticand heterocyclic groups can be connected to the C₀₋₆ alkyl group via anyposition on the fused ring, or the aromatic or heterocyclic groups. Forexample, the aromatic group or heterocyclic group may by directlyconnected to the group W through a chemical bond to a carbon or nitrogenposition, or connected via an alkyl group to a carbon or nitrogenposition, or connected via an alkyl group to the nitrogen, oxygen orsulfur of an amino, hydroxyl or thiol substituent. The optionalsubstituents for the fused or unfused aromatic or heterocyclic ring areidentical to those described for Rings A and B above.

[0075] In the above Formula I, Z may be (4) an optionally substitutedC₀₋₆ alkyl or C₃₋₇ cycloalkyl amino group. Examples of the optionallysubstituted C₀₋₆ alkyl amino groups include straight or branched chainsincluding methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino etc. Encompassed in the present invention arealso optionally substituted C₃₋₇ cycloalkyl amino groups such ascyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylaminoetc. The amino group may be substituted with an optionally substitutedC₁₋₆ alkyl group, a C₀₋₆ alkyl group substituted with an optionallysubstituted, fused or unfused aromatic group or heterocyclic group. Thearomatic groups and heterocyclic groups are defined in (3) above. Theamino group may be substituted once or twice (to form a secondary ortertiary amine) with the groups described above and may be identical ornon-identical. The amino group may also be the nitrogen atom of aguanidine, carbamate or urea group. The optional substituents areidentical to those described above for Rings A and B.

[0076] In the above Formula I, Z may be (5) an optionally substitutedcarbonyl or sulfonyl group. For example, the carbonyl or sulfonyl groupmay be substituted with an optionally substituted straight, cyclic orbranched alkyl groups, e.g. a C₁₋₇ alkylgroup such as acetyl, propionyl,cyclopropanoyl, cyclobutanoyl, isopropanoyl, isobutanoyl etc. ormethanesulfonyl, ethanesulfonyl etc. or an optionally substitutedaromatic or heterocyclic carbonyl or sulfonyl group such as benzoyl,pyridinecarbonyl, benzenesulfonyl etc. The aromatic and heterocyclicgroups are the same as defined for (3) above. The optionally substitutedcarbonyl or sulfonyl group may also be an optionally substituted C₁₋₆alkyl aromatic or heterocyclic group such as defined in (3) above,exemplified by phenylacetyl, phenylpropanoyl, pyridineacetyl,pyridinepropanoyl, phenylmethanesulfonyl etc., or the carbonyl of anoptionally substituted amino acid derivative. The carbonyl may also bethe carbonyl group of a urea or carbamate in which an optionallysubstituted C₁₋₆ alkyl or C₁₋₆ alkyl group optionally substituted withan aromatic or heterocyclic group (as defined in (3) above) is connectedto nitrogen or oxygen, respectively. The optional substituents areidentical to those described above for Rings A and B.

[0077] The invention also provides a compound of Formula I

[0078] In which, W, Y, n, n′, Ar, R¹-R⁸ are defined as above,

[0079] X and Z are independently selected from H, optionally substitutedC₁₋₆ alkyl or C₀₋₆ alkaryl or C₀₋₆ alkylheterocyclyl groups. The X and Zgroups may also bind each other to form an optionally substituted 5- to7-membered cyclic amine group such as tetrahydropyrrole, pyrrolidine,piperazine, homopiperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole etc., or an optionally substituted pyran, thiopyranor cycloalkyl ring etc.

[0080] The optional substituents are defined as above.

[0081] The novel compounds of the present invention may be formulated aspharmaceutical compositions that may be administered topically;percutaneously, including intravenously; orally; and by other standardroutes of pharmaceutical administration to mammalian subjects asdetermined according to routine clinical practice. The compounds of thepresent invention are useful as agents demonstrating protective effectson target cells from HIV infection (Blanco et al., Antimicrob. Agts. andChemother. 44: 51-56, 2000). The compounds of the present invention aremay serve to interfere with the binding of natural ligands to chemokinereceptors on a wide range of cell populations, including chemokinereceptors CXCR4 and CCR5 as well as other chemokine receptors of theC-X-C and C-C motifs. The compounds of the present invention areconsidered further useful as antagonists or agonists of such chemokinereceptors. Such chemokine antagnoist agents capable of interfering inthe chemokine binding to its respective chemokine receptor would beuseful to reconstitute the immune system by increasing the level of CD4⁺cells (Biard-Piechaczyk, et al., Immunol. Lett., 70: 1-3 1999); asantagonist agents of apoptosis in immune cells, such as CD8⁺ cells(Herbin, et al., Nature 395: 189-193, 1998), and as antagonist agents ofapoptosis in neuronal cells (Ohagen et al., J. of Virol., 73: 897-906,1999; and Hesselgesser, et al., Curr. Biol. 8: 595-598, 1998). Chemokinereceptor antagonist agents would be useful to inhibit the migration ofhuman bone marrow B lineage cells to stromal-derived factor 1 (See, forexample: E. Fedyk, et al., J. of Leukocyte Biol., 66:667-673, 1999), aswell as other biological activities related to the ability of thesecompounds to inhibit the binding of chemokines to their respectivereceptors.

[0082] Anti-HIV Assays.

[0083] Compounds were tested for their ability to inhibit HIV-1replication in MT-4 cells or PBMC's (peripheral blood mononucleocytes)using published procedures (for example, see: Labrosse et al. J. Virol.1998, 6381-6388; Simmons et al. J. Virol. 1998, 8453-8457; Donzella etal. Nature Medicine 1998, 72-77; Schols et al. J. Exp. Med. 1997,1383-1388; De Clercq et al. Antiviral Res. 1997, 147-156; and Bridger etal. U.S. patent application Ser. No. 09/111,895). In addition to theabove references, experimental methods for performing anti-viral assayscan also be found in: Bridger et al. J. Med. Chem. 1995, 38, 366-378;Bridger et al. J. Med. Chem. 1996, 39, 109-119; Bridger et al. U.S. Pat.No. 5,698,546; Bridger et al. U.S. Pat. No. 5,583,131; Bridger et al.U.S. Pat. No. 5,817,807; De Clercq et al. Antimicrob. Agents andChemother. 1994, 38, 668-674.

[0084] These assays were considered representative of inhibition viabinding to the chemokine receptors CXCR4 and CCR5 respectively due toprior inhibition studies and the following inherent properties of thecells and viruses:

[0085] 1. The HIV-1 strains NL4.3 and III_(B) are T-tropic strains thatexclusively use CXCR4 as the co-receptor for entry into cells. MT-4Cells express CXCR4 but not CCR5.

[0086] The HIV-1 strain BaL is M-tropic (macrophage tropic) strain thatexclusively uses CCR5 as a co-receptor for entry into cells. PBMC's(from healthy donors) express all chemokine receptors including CXCR4and CCR5.

[0087] Prior mechanistic studies that characterize the directinteraction of1,1′-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecaneoctahydrochloride dihydrate (described in U.S. Pat. No. 5,583,131) andrelated compounds with the chemokine receptors CXCR4 and CCR5 can befound in references as cited supra.

[0088] Preparation of Starting Materials and General Procedures.

AMD7088: Preparation ofN-(2-nitrobenzenesulfonyl)-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine

[0089] 2-Aminomethylpyridine (34.76g, 315 mmol) andterephthaldicarboxaldehyde (20.32 g, 150 mmol) were refluxed in benzene(500 mL) in a Dean Stark apparatus, overnight. The benzene was removedin vacuo and the bis-imine residue was taken up in dry methanol (250 mL)and transferred to a Parr bottle. To the solution was added 10%palladium on carbon (7.63 g) and the mixture was hydrogenated at 30 psihydrogen, for 20 hours. The product mixture was filtered through celiteand concentrated in vacuo to give an orange oil (47.62 g, 100%). Withoutfurther purification, the orange oil (46.8 g, 147 mmol) was dissolved indry dichloromethane (1300 mL) and triethylamine (20.3 g, 199 mmol).2-Nitrobenzenesulfonyl chloride (30.3g, 132 mmol) was added in oneportion to the stirred solution, and after one hour, the mixture waswashed with water and brine, dried over MgSO₄ and concentrated to anolive-brown oil (79.09 g). The product was purified by columnchromatography on silica gel (4% MeOH in CH₂Cl₂) to give AMD7088 (16.02g): ¹H NMR (300 MHz, CDCl₃) δ 8.55 (d, 1H, J=5 Hz), 8.38 (d, 1H, J=5Hz), 7.95 (d, 1H, J=9 Hz), 7.45-7.70 (m, 5H), 7.05-7.30 (m, 8H), 4.58(s, 4H), 3.88 (s, 2H), 3.77 (s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ 159.9,156.4, 149.7, 149.6, 148.6, 140.2, 137.0, 136.9, 134.3, 134.2, 133.7,132.0, 131.4 (2C), 129.1 (2C), 128.9, 124.6, 122.8 (2C), 122.7, 122.4,54.8, 53.4, 52.6, 51.9. ES-MS m/z 504.2 (M+H). Anal Calcd for(C₂₆H₂₄N₅O₄S) 0.7(H₂O): C, 60.62; H, 4.97; N, 13.59. Found: C, 60.73; H,4.99; N, 13.49.

AMD7090: Preparation ofN-(2-nitrobenzenesulfonyl)-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine

[0090] In a similar manner, 2-pyridinecarboxaldehyde (32.46 g, 0.30 mol)and m-xylenediamine (20.64g, 0.15 mol) were stirred in dry methanol (500mL) at 30° C. ¹H NMR indicated consumption of the starting aldehydeafter 1 hour. The mixture was then concentrated to approximately halfvolume, treated with 10% Pd on carbon (5.0 g), and the mixture washydrogenated at 30 psi hydrogen, overnight. The reaction mixture wasfiltered through celite, concentrated in vacuo, and the residuedissolved in dry dichloromethane. To this solution was addedtriethylamine (15.33 g, 150 mmol) followed by a solution of2-nitrobenzenesulfonyl chloride (30.84 g, 135 mmol) in drydichloromethane (200 mL) dropwise with vigorous stirring. The reactionwas allowed to stir overnight at room temperature and the solution wasthen washed with water (2×500 mL) and brine (1000 mL), dried (MgSO₄),and concentrated to give a red-brown oil (73.64g). The product waspurified by column chromatography on silica gel (4% MeOH in CH₂Cl₂) togive AMD7090 (31.34 g, 46% overall yield). ¹H NMR (300 MHz, CDCl₃) δ8.55 (d, 1H, J=5 Hz), 8.38 (d, 1H, J=5 Hz), 7.94 (d, 1H, J=9 Hz),7.45-7.70 (m, 5H), 7.05-7.30 (m, 8H), 4.60 (s, 4H), 3.85 (s, 2H), 3.71(s, 2H); ¹³C NMR (75.5 MHz, CDCl₃) δ 159.8, 156.3, 149.7, 149.6, 148.3,140.8, 137.0, 136.9, 135.6, 134.5, 133.7, 132.0, 131.4, 129.1, 128.8,128.3, 127.7, 124.5, 122.9, 122.8, 122.7, 122.4, 54.8, 53.5, 52.7, 52.1.ES-MS m/z 504.2 (M+H). Anal Calcd for (C₂₆H₂₄N₅O₄S) 0.7(H₂O): C, 60.62;H, 4.97; N, 13.59. Found: C, 60.58; H, 5.00; N, 13.44.

AMD7089: Preparation ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-[2-(2-pyridinyl)ethyl]-1,4-benzenedimethanamine

[0091] To a stirred solution ofN-[1-Methylene-4-(hydroxymethylene)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(see Bridger et al. U.S. patent application Ser. No. 09/111,895) (30.0g,72.5 mmol) in dichloromethane (300 mL) was added manganese oxide (63.0g, 725 mmol, 10 Equiv.) and the reaction mixture was allowed to stirovernight at room temperature. The mixture was filtered through celite,and concentrated to give 30.1 g (100%) of the desired aldehyde as alight yellow solid. Without further purification, the aldehyde (72.5mmol) was dissolved in methanol (500 mL) and to this solution was added2-(2-aminoethyl)-pyridine (10.63 g, 87 mmol) and the mixture was heatedto 40° C. with stirring until the starting aldehyde was consumed by ¹HNMR analysis. The solution was cooled to room temperature and sodiumcyanoborohydride (9.62 g, 145 mmol) was added in one portion. Thereaction mixture was stirred for one hour, quenched with 0.1N sodiumhydroxide (500 mL) and the methanol was then evaporated in vacuo. Theaqueous solution was extracted with ethyl acetate (3×500 mL) and thecombined organic extracts were washed with water and brine, dried(MgSO₄) and concentrated to give 36.12 grams of crude product. Theproduct was purified by column chromatography on silica gel (4% MeOH inCH₂Cl₂) to give AMD7089 (16.32 g, 43% overall yield) as a yellow oil. ¹HNMR (300 MHz, CDCl₃) δ 8.55 (d, 1H, J=5 Hz), 8.38 (d, 1H, J=5 Hz), 7.94(d, 1H, J=9 Hz), 7.45-7.70 (m, 5H), 7.00-7.20 (m, 8H), 4.57 (s, 4H),3.79 (s, 2H), 3.02 (s, 4H); ¹³C NMR (75.5 MHz, CDCl₃) δ 160.2, 156.2,149.6, 149.5, 148.3, 138.2, 137.1, 137.0, 134.9, 134.5, 133.7, 132.0,131.4, 139.3 (2C), 129.1 (2C), 124.6, 123.8, 122.9, 122.8, 122.0, 53.1,52.7, 51.9, 48.5, 36.9. ES-MS m/z 518.3 (M+H). Anal Calcd for(C₂₇H₂₆N₅O₄S) 0.6(H₂O): C, 61.49; H, 5.20; N, 13.28. Found: C, 61.44; H,5.25; N, 13.32.

AMD7091: Preparation ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N-[2-(2-pyridinyl)ethyl]-1,3-benzenedimethanamine

[0092] AMD7091 (the meta-analog of AMD7089) was prepared in a similarmanner. Thus, the corresponding meta-alcohol gave AMD7091 (21.6 g, 26%overall yield): ¹H NMR (300 MHz, CDCl₃) δ 8.55 (d, 1H, J=5 Hz), 8.38 (d,1H, J=5 Hz), 7.94 (d, 1H, J=9 Hz), 7.45-7.70 (m, 5H), 7.00-7.20 (m, 8H),4.57 (s, 4H), 3.69 (s, 2H), 3.42 (s, 2H), 2.97(s, 2H); ¹³C NMR (75.5MHz, CDCl₃) δ 160.5, 156.3, 149.6, 149.5, 148.3, 140.8, 137.0, 136.9,135.6, 134.4, 133.7, 132.0, 131.3, 129.0, 128.7, 128.1, 127.6, 124.5,123.7, 122.8, 122.7, 121.7, 53.8, 52.8, 52.2, 49.1, 38.5. ES-MS m/z519.1 (M+H). Anal Calcd for (C₂₇H₂₆N₅O₄S) 0.4(H₂O): C, 61.79; H, 5.34;N, 13.34. Found: C, 61.79; H, 5.39; N, 13.10.

AMD7474: Preparation of 8-hydroxy-5,6,7,8-tetrahydroquinoline

[0093] To a stirred solution of 5,6,7,8-tetrahydroquinoline (74.3 g,0.558 mol) in glacial acetic acid (275 mL) at room temperature was added30% H₂O₂ (55 mL) and the solution was heated to 70° C. After 6 hours,the reaction mixture was cooled to room temperature, additional H₂O₂ (55mL) was added, and the solution was heated at 70° C. overnight. Thereaction mixture was cooled to room temperature and concentrated underreduced pressure. The residue was dissolved in CHCl₃ (300 mL) andtreated with solid Na₂CO₃ (175 g). After 1 hour, the supernatant wasdecanted and the residue was washed with warm CHCl₃ (3×300 mL). Thecombined supernatants were filtered and concentrated to provide 121 g ofa yellow oil. The oil was dissolved in acetic anhydride (400 mL) andheated at 90° C. overnight. The mixture was cooled to room temperatureand concentrated. Distillation (Kugelrohr, bp 110-140° C. @ 1 Torr) ofthe resultant oil provided 99.2 g of8-acetoxy-5,6,7,8-tetrahydroquinoline.

[0094] To a solution of 8-acetoxy-5,6,7,8-tetrahydroquinoline (99.2 g)in methanol (450 mL) was added K₂CO₃ (144 g, 1.04 mol) and the mixturewas stirred at room temperature overnight. The mixture was poured intowater (500 mL) and extracted with CHCl₃ (3×500 mL) and the combinedorganic extracts were dried (Na₂SO₄), and concentrated to provide 71.6 gof 8-hydroxy-5,6,7,8-tetrahydroquinoline as a brown oil. A purifiedsample (silica gel, 25:1 CH₂Cl₂-CH₃OH) exhibited the following spectralproperties: ¹H NMR (CDCl₃) δ 1.75-1.89 (m, 2H), 1.96-2.06 (m, 1H),2.25-2.33 (m, 1H), 2.74-2.90 (m, 2H), 4.23 (br s, 1H, OH), 4.72 (dd, 1HJ=7.8, 6.3 Hz), 7.12 (dd, 1H, J=7.5, 4.8 Hz), 7.41 (d, 1H, J=7.5 Hz),8.41 (d, 1H, J=4.8 Hz); ¹³C NMR (CDCl₃) δ 19.60, 28.84, 31.27, 68.87,122.74, 132.19, 137.40, 147.06, 158.50. ES-MS m/z 150 (M+H).

[0095] In a similar manner:

[0096] Cyclopentenopyridine gave7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine (AMD 7473). ¹H NMR(CDCl₃) δ 2.01-2.13 (m, 1H), 2.50-2.61(m, 1H), 2.78-2.89 (m, 1H), 3.06(ddd, 1H, J=15.9, 9.0, 4.2 Hz), 4.85 (br s, 1H, OH), 5.25 (t, 1H J=6.9Hz), 7.15 (dd, 1H, J=7.5, 4.8 Hz), 7.57 (d, 1H, J=7.5 Hz), 8.43 (d, 1H,J=4.8 Hz); ¹³C NMR (CDCl₃) δ 27.90, 33.17, 74.46, 123.07, 133.86,136.97, 148.05, 165.50. ES-MS m/z 136 (M+H).

[0097] Cycloheptenopyridine gave9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (AMD7475). ¹H NMR(CDCl₃) δ 1.17-1.30 (m, 1H), 1.34-1.48 (m, 1H), 1.81-2.11 (m, 3H), 2.23(br d, 1H, J=13.5 Hz), 2.72-2.76 (m, 2H), 4.76 (d, 1H, J=11.1 Hz), 5.94(s, 1H, OH), 7.12 (dd, 1H, J=7.2, 4.8 Hz), 7.44 (d, 1H, J=7.2 Hz), 8.36(d, 1H, J=4.8 Hz); ¹³C NMR (CDCl₃) δ 27.44, 29.41, 34.71, 36.72, 72.57,122.45, 136.05, 137.56, 144.75, 161.38. ES-MS m/z 164 (M+H).

AMD7488: Preparation of 8-amino-5,6,7,8-tetrahydroquinoline

[0098] To a stirred solution of 8-hydroxy-5,6,7,8-tetrahydroquinoline(71.6 g, 0.480 mol) in CH₂Cl₂ (500 mL, 1.0 M) at room temperature wasadded triethylamine (126 mL, 0.904 mol) followed by methanesulfonylchloride (55 mL, 0.711 mol). The resulting mixture was heated to 40° C.overnight then cooled to room temperature. The mixture was poured intowater (350 mL), diluted with CH₂Cl₂ (350 mL), and the phases wereseparated. The organic phase was washed with brine (2×250 mL), dried(Na₂SO₄), and concentrated. The resultant oil was dissolved in DMF (570mL), treated with sodium azide (63.1 g, 0.971 mol), and heated at 70° C.overnight. The mixture was cooled to room temperature, then evaporatedand the residual slurry was poured into brine (500 mL) and extractedwith ether (4×500 mL). The combined organic extracts were washed withbrine (2×100 mL), dried (Na₂SO₄), and concentrated. The crude materialwas filtered through a short plug of silica gel (CH₂Cl₂) to provide 41.0g (46% from 5,6,7,8-tetrahydroquinoline) of8-azido-5,6,7,8-tetrahydroquinoline as a red oil.

[0099] To a solution of the azide (41.0 g, 0.256 mol) in methanol (250mL) was added Pd/C (10%, 4.1 g) and the mixture was hydrogenated at 30psi on a Parr shaker. The mixture was filtered through celite and thecake was washed with methanol. The combined filtrates were evaporatedand the residual oil was distilled (Kugelrohr, bp 115-140° C. @ 0.2Torr) to provide 26.8 g (71%) of 8-amino-5,6,7,8-tetrahydroquinoline(AMD7488) as a pale yellow oil. ¹H NMR (MeOH-d₄) δ 1.81-1.98 (m, 2H),2.03-2.15 (m, 1H), 2.38-2.46 (m, 1H), 2.88-2.92 (m, 2H), 4.41 (dd, 1H,J=9.3, 6.3 Hz), 7.30 (dd, 1H, J=7.5, 4.5 Hz), 7.62 (d, 1H, J=7.5 Hz),8.47 (d, 1H, J=4.5 Hz); ¹³C NMR (MeOH-d₄) δ 21.12, 28.72, 28.89, 52.28,124.86, 134.35, 138.96, 148.49, 152.57. ES-MS m/z 149 (M+H).

[0100] In a similar manner:

[0101] 7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine gave7-amino-6,7-dihydro-5H-cyclopenta[b]pyridine. ¹H NMR (CDCl₃) δ 1.72-1.82(m, 3H), 2.54-2.59 (m, 1H), 2.79-2.94 (m, 2H), 4.33 (dd, 1H, J=9.0, 9.0Hz), 7.09 (dd, 1H, J=7.5, 4.8 Hz), 7.52 (d, 1H, J=7.5 Hz), 8.41 (d, 1H,J=4.8 Hz).

[0102] 9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine gave9-amino-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine. ¹H NMR (MeOH-d₄) δ1.24-1.36 (m, 1H), 1.56-1.68 (m, 1H), 1.89-2.17 (m, 4H), 2.85-2.89 (m,2H), 4.63 (d, 1H, J=11.4 Hz), 7.26 (dd, 1H, J=7.5, 4.5 Hz), 7.64 (d, 1H,J=7.5 Hz), 8.41 (br d, 1H, J=4.5 Hz). ¹³C NMR (MeOH-d₄) δ 27.81, 30.45,33.18, 34.57, 55.97, 124.43, 137.80, 138.90, 147.03, 157.34. ES-MS m/z163 (M+H).

AMD8760: Preparation ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine

[0103] General Procedure A: Direct Reductive Amination with NaBH₃CN

[0104] To a stirred solution of the amine (1 equivalent) in anhydrousmethanol (concentration ˜0.1 M), at room temperature, was added thecarbonyl compound (˜1-2 equivalents) in one portion. Once the carbonylhad dissolved (˜5 minutes), NaBH₃CN (˜2-4 equiv.) was added in oneportion and the resultant solution was stirred at room temperature. Thesolvent was removed under reduced pressure and CH₂Cl₂ (20 mL/mmol ofamine) and brine or 1.0 M aqueous NaOH (10 mL/mmol amine) were added tothe residue. The phases were separated and the aqueous phase wasextracted with CH₂Cl₂ (3×10 mL/mmol amine). The combined organic phaseswere dried (Na₂SO₄) and concentrated. The crude material was purifiedchromatography.

[0105] Using General Procedure A:

[0106] Reaction ofN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(21.2 g, 51 mmol) with 8-amino-5,6,7,8-tetrahydroquinoline (7.61 g, 51mmol) followed by column chromatography on silica gel (5% MeOH/CH₂Cl₂)gave the title compound (11.0 g, 40%) as an orange oil. ¹H NMR (CDCl₃) δ1.74-1.84 (m, 2H), 1.99-2.05 (m, 1H), 2.02-2.05 (m, 1H), 2.72-2.86 (m,2H), 3.13 (br s, 1H), 3.79-3.94 (m, 3H), 4.57 (s, 2H), 4.60 (s, 2H),7.07-7.11 (m, 4H), 7.20-7.24 (m, 3H), 7.37 (d, 1,H, J=7.4 Hz), 7.53, (t,2H, J=8.4 Hz) 7.64 (br s, 2H), 7.94 (d, 1H, J=7.8 Hz), 8.40 (t, 2H,J=5.9 Hz); ¹³C NMR (CDCl₃) δ 19.70, 28.61, 28.85, 51.43, 51.54, 52.37,57.56, 122.26, 122.78, 122.82, 124.55, 128.91 (2), 129.12 (2), 131.39,131.98, 132.87, 133.65, 133.98, 134.60, 136.98, 137.28, 140.87, 147.20,148.30, 149.60, 156.34, 157.77. ES-MS m/z 544 (M+H). Anal. Calcd. forC₂₉H₂₉N₅O₄S.0.1CH₂Cl₂: C, 63.30; H, 5.33; N, 12.68. Found: C, 63.53; H,5.35, N, 12.58.

[0107] Resolution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(56,7,8-tetrahydro-8-guinolinyl)-1,4-benzenedimethanamine.

[0108] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(1.641 g, 3.02 mmol) in CH₂Cl₂ (10 mL) was added (S)-(−)-1-phenylethylisocyanate (0.50 mL, 3.57 mmol) and the mixture stirred at roomtemperature for 2 hours. The reaction mixture was poured into brine (40mL) and diluted with CH₂Cl₂ (15 mL). The phases were separated and theaqueous phase was extracted with CH₂Cl₂ (4×15 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification and separation of the resulting mixture ofdiastereomeric ureas by column chromatography on silica gel(CH₂Cl₂/i-PrOH, 97.5/2.5) afforded a low polarity diastereomer (0.790 g,38%) and a high polarity diastereomer (0.740 g, 35%), both as orangefoams.

[0109]¹H NMR (CDCl₃): low polarity diastereomer: δ 1.31 (d, 3H, J=6 Hz),1.82-1.90 (m, 2H), 1.94-1.99 (m, 1H), 2.18-2.22 (m, 1H), 2.73 (br s,2H), 4.15 (d, 1H, J=18 Hz), 4.31 (d, 1H, J=18 Hz), 4.55 (s, 2H), 4.58(s, 2H), 4.98-5.03 (m, 2H), 5.49-5.52 (br m, 1H), 7.03-7.31 (m, 12H),7.34 (d, 1H, J=6.9 Hz), 7.50-7.60 (m, 2H), 7.62-7.68 (m, 2H), 7.99 (d,1H, J=7.5 Hz), 8.41 (br s, 2H).

[0110]¹H NMR (CDCl₃): high polarity diastereomer: δ 1.32 (d, 3H, J=6Hz), 1.76-1.83 (m, 2H), 1.93-1.98 (m, 1H), 2.14-2.19 (m, 1H), 2.72 (brs, 2H), 4.08 (d, 1H, J=18 Hz), 4.33 (d, 1H, J=18 Hz), 4.54 (s, 2H), 4.59(s, 2H), 4.97-5.01 (m, 2H), 5.54-5.59 (br m, 1H), 7.05-7.28 (m, 12H),7.35 (d, 1H, J=7.8 Hz), 7.49-7.57 (m, 2H), 7.62-7.68 (m, 2H), 7.98 (d,1H, J=7.5 Hz), 8.41 (d, 1H, J=4.2 Hz), 8.45 (d, 1H, J=4.8 Hz).

[0111] The diastereomeric purity of the urea's was determined byreversed phase HPLC using the following conditions: Instrument: HewlettPackard 1100 HPLC (VWD2); Column: Zorbax SB, C8, 3.5 μm (100 A), 150mm×3.0 mm; Mobile Phases: A: H₂O, B: MeCN; Gradient: 50% B (0 min), 80%B (20 min), 50% B (21 min); Total Run Time: 40 min; Flow Rate: 0.350mL/min; Temperature: 40° C.;

[0112] Detector: UV @ 254 nm; Injection volume: 5 μL.

[0113] Retention time of the low polarity diastereomer=13.8 min (100%de).

[0114] Retention time of the high polarity diastereomer=13.2 min (100%de).

[0115] Acid Hydrolysis of the Diastereomerically Pure Urea Derivatives.

[0116] A stirred solution of the low polarity diastereomer (0.600 g,0.867 mmol) in EtOH/concentrated HCl (6:1, 28 mL) was heated to refluxuntil the starting material had been consumed by TLC (24.5 hours). Themixture was cooled to room temperature, concentrated under reducedpressure and partitioned between CH₂Cl₂ (25 mL) and 1 N NaOH (40 mL).The aqueous phase was washed with CH₂Cl₂ (2×25 mL) and the combinedorganic layers were dried (Na₂SO₄), filtered and concentrated in vacuo.

[0117] To a solution of the resultant crude product from above (3 mg) inCH₂Cl₂ (1 mL) was added (S)-(−)-1-phenylethyl isocyanate (5 μL, 0.036mmol) and the mixture was stirred overnight (16 hours). The reaction wasconcentrated and the crude urea was analyzed by HPLC using theconditions described above to give a diastereomeric ratio of 17.6:1(5.4% racemization had occurred during hydrolysis of the urea).

[0118] The remainder of the crude product from above was purified bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 96:4 to 9:1) to affordan enantiomerically enriched sample ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.286 g, 61% yield, 89% ee) as a pale yellow foam. ¹H NMR (CDCl₃) δ1.59 (br s, 1H), 1.72-1.81 (m, 2H), 2.00-2.05 (m, 1H), 2.16-2.20 (m,1H), 2.76-2.86 (m, 2H), 3.79-3.83 (m, 1H), 3.81 (d, 1H, J=12 Hz), 3.93(d, 1H, J=15 Hz), 4.57 (s, 2H), 4.60 (s, 2H), 7.07-7.11 (m, 4H),7.20-7.24 (m, 3H), 7.37 (d, 1H, J=7.4 Hz), 7.51-7.57 (m, 2H), 7.61-7.67(m, 2H), 7.94 (d, 1H, J=7.8 Hz), 8.40 (br t, 2H, J=5.9 Hz).

[0119] Similarly, a stirred solution of the higher polarity diastereomer(0.400 g, 0.578 mmol) in EtOH/concentrated HCl (6:1, 28 mL) was heatedto reflux until the starting material had been consumed by TLC (24.5hours). The reaction was worked-up and a small sample was reacted with(S)-(−)-1-phenylethyl isocyanate as described above. Analysis of thecrude urea by HPLC gave a diastereomeric ratio of 12.6:1 (7.4%racemization had occurred during hydrolysis of the urea). The remainderof the crude product was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 96:4 to 9:1) to afford an enantiomerically enriched sampleofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.241 g, 77% yield, 85% ee) as a pale yellow foam.

AMD8812: Preparation ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine

[0120] Using General Procedure A:

[0121] Reaction of the aldehyde from above (26.9 g, 66 mmol) with9-amino-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (10.6 g, 66 mmol)followed by column chromatography on silica gel (5% MeOH/EtOAc) gave thetitle compound (16.9 g, 46%) as a white foam. ¹H NMR (CDCl₃) δ 1.39-1.60(m, 2H), 1.69-1.77 (m, 2H), 2.01-2.08 (m, 2H), 2.70 (t, 1H, J=12.0 Hz),2.85-2.91 (m, 1H), 3.25 (br s, 1H), 3.76 (q, 2H, J=12.0 Hz), 3.95 (d,1H, J=9.0 Hz), 4.57 (br s, 4H), 7.02-7.23 (m, 7H), 7.35 (d, 1H, J=7.4Hz), 7.52-7.64 (m, 4H) 7.94 (d, 1H, J=7.7 Hz), 8.37 (dd, 2H, J=11.4, 4.4Hz); ¹³C NMR (CDCl₃) δ 27.68, 29.20, 33.84, 34.62, 51.87, 52.13, 52.54,63.08, 122.12, 122.74, 122.87, 124.57, 128.98 (2), 129.07 (2), 131.36,132.08, 133.77, 134.01, 134.49, 137.02, 137.43 (2), 140.68, 146.13,148.27, 149.64, 156.23, 162.10. ES-MS m/z 558 (M+H). Anal. Calcd. forC₃₀H₃₁N₅O₄S.0.3CH₂Cl₂: C, 62.41; H, 5.46; N, 12.01. Found: C, 62.63; H,5.54; N, 12.17.

AMD8840:N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine

[0122] Using General Procedure A:

[0123] Reaction ofN-[1-methylene-3-(carboxaldehyde)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(36.0 g, 87 mmol) with 8-amino-5,6,7,8-tetrahydroquinoline (12.9 g, 87mmol) followed by column chromatography on silica (EtOAc) gave the titlecompound (17.5 g, 47%) as a yellow foam. ¹H NMR (CDCl₃) δ 1.73-1.79 (m,2H), 1.99-2.05 (m, 1H), 2.11-2.19 (m, 1H), 2.71-2.83 (m, 2H), 3.72-3.88(m, 3H), 4.59 (s, 2H), 4.63 (s, 2H), 7.03-7.11 (m, 4H), 7.17 (t, 1H,J=6.9 Hz), 7.25 (d, 2H, 7.0 Hz), 7.32 (d, 1H, J=7.4 Hz), 7.51-7.61 (m,4H), 7.95 (d, 1H J=7.8 Hz), 8.40 (t, 2H, J=5.9 Hz); ¹³C NMR (CDCl₃) δ19.61, 28.59, 28.86, 51.59, 51.70, 52.58, 57.60, 60.40, 121.87, 122.35,122.42, 124.14, 127.03, 127.84, 128.38, 128.63, 130.99, 131.57, 132.49,133.23, 134.14, 135.08, 136.59, 136.88, 141.13, 146.79, 147.86, 149.18,156.00, 157.40. ES-MS m/z 544 (M+H). Anal. Calcd. forC₂₉H₂₉N₅O₄S.0.1CH₃COOCH₂CH₃: C, 63.92; H, 5.44; N, 12.68. Found: C,63.65; H, 5.47; N, 12.42.

AMD8843: Preparation ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,3-benzenedimethanamine

[0124] General Procedure B: Direct Reductive Amination with NaBH(OAc)₃

[0125] To a stirred solution of the amine (1 equivalent) in CH₂Cl₂(concentration ˜0.2 M), at room temperature, was added the carbonylcompound (˜1-2 equivalents), glacial acetic acid (0-2 equivalents) and,NaBH(OAc)₃ (˜1.5-3 equiv.) and the resultant solution was stirred atroom temperature. The reaction mixture was poured into either saturatedaqueous NaHCO₃ or 1.0 M aqueous NaOH (10 mL/mmol amine). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×10 mL/mmolamine). The combined organic phases were dried (Na₂SO₄) andconcentrated. The crude material was purified chromatography.

[0126] Using General Procedure B:

[0127] Reaction of the aldehyde from above (22.3 g, 54 mmol) with9-amino-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (8.8 g, 54 mmol)followed by column chromatography on silica gel (5% MeOH/EtOAc) gave thetitle compound (AMD8843) (22.1 g, 73%) as a yellow oil. ¹H NMR (CDCl₃) δ1.42-1.61 (m, 2H), 1.75-1.80 (m, 2H), 2.03 (d, 2H, J=13.8 Hz), 2.54 (brs, 1H), 2.71 (t, 1H, J=12.0 Hz), 2.86-2.93 (m, 1H), 3.72 (q, 2H, J=12.0Hz), 3.92 (d, 1H, J=10.5 Hz), 4.58 (s, 2H), 4.61 (s, 2H), 7.03-7.24 (m,7H), 7.35 (d, 1H, J=7.4 Hz), 7.51-7.62 (m, 4H) 7.93 (d, 1H, J=7.7 Hz),8.38 (dd, 2H, J=8.0, 4.4 Hz); ¹³C NMR (CDCl₃) δ 27.34, 28.69, 33.55,34.23, 51.75, 51.93, 52.47, 62.77, 121.59, 122.33, 122.42, 124.11,126.95, 127.84, 128.41, 128.57, 130.99, 131.56, 133.23, 134.15, 135.01,136.57, 136.93, 137.05, 141.35, 145.75, 147.86, 149.18, 155.96, 162.13.ES-MS m/z 558 (M+H). Anal. Calcd. for C₃₀H₃₁N₅O₄S: C, 64.61; H, 5.60; N,12.56. Found: C, 64.80; H, 5.69; N, 12.30.

[0128] Preparation ofN-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine.

[0129] 4-[[(2-pyridinylmethyl)amino]methyl]benzyl alcohol

[0130] Terephthaldicarboxaldehyde (40.75 g, 0.304 mol), methanol (250mL), palladium on activated carbon, (10%, 4.24 g) and2-(aminomethyl)pyridine (3.1 mL, 0.003 mol, 0.01 mol equiv) werecombined in a hydrogenation vessel and the reaction mixture was shakenon a Parr hydrogenator for 3.5 hours at 38 psi of hydrogen. The mixturewas filtered through celite and the cake was washed with methanol. Thesolution was dried over Na₂SO₄, filtered, then reduced in volume to ˜200mL under reduced pressure. To this stirred solution is then added asolution of 2-(aminomethyl)pyridine (28 mL, 0.272 mol, 0.9 mol. Equiv.)in methanol (50 mL) over 15 minutes. This was allowed to stir overnightat room temperature. The solution was transferred to a hydrogenationflask and palladium on activated carbon (10%, 2.60 g, 0.06) was addedand the flask was shaken on a Parr hydrogenator for 4 hours at 39 psi ofhydrogen. The mixture was filtered through celite and the cake waswashed with methanol. The filtrates were then evaporated and the crudematerial was filtered through silica gel (180 g, 9:1 CH₂Cl₂:CH₃OH) toprovide the title compound (67.45 g, 93%) as a yellow oil. ¹H NMR(CDCl₃) δ 2.28 (br, 2H), 3.82 (s, 2H), 3.90 (s, 2H), 4.65 (s, 2H), 7.16(br t, 1 H, J=6.0 Hz), 7.26-7.35 (m, 5H), 7.64 (td, 1H, J=7.7, 1.7 Hz),8.54 (br d, 1H, J=4.5 Hz).

[0131]4-[[N-(-t-butoxycarbonyl)-N-(2-pyridinylmethyl)amino]methyl]benzylalcohol

[0132] To a stirred solution of the alcohol from above (17.39 g, 76.3mmol) in THF (260 mL) was added triethylamine (10 drops) and distilledwater (10 drops). Di-tert-butyl dicarbonate (19.93 g, 91.3 mmol, 1.2 molequiv) was added dropwise and the reaction mixture was stirred for 4hours at room temperature. Distilled water (250 mL) and ethyl acetate(250 mL) were added and the phases separated. The aqueous phase waswashed with ethylacetate (2×250 mL) and the combined organic phases weredried (Na₂SO₄) and filtered. The solvent was removed from the filtrateunder reduced pressure to give the crude product (30.62 g) as a yellowoil. This crude product was purified by chromatography on silica gel(19:1 CH₂Cl₂:CH₃OH). The impure fractions were re-purified on silica gel(49:1 CH₂Cl₂:CH₃OH) to give the desired alcohol (21.57 g, 86%) as ayellow oil.¹H NMR (CDCl₃) δ 1.42 (br s) and 1.49 (br s) (total 9H), 4.45(br s) and 4.53 (br s) (total 4H), 4.67 (s, 2H), 7.15-7.33 (m, 6H), 7.64(td, 1H, J=7.7, 1.5 Hz), 8.50 (br d, 1H, J=4.8 Hz).

[0133]4-[[N-(-t-butoxycarbonyl)-N-(2-pyridinylmethyl)amino]methyl]benzylaldehyde

[0134] To a stirred solution of the alcohol from above (4.59 g, 14.0mmol) in dichloromethane (250 mL) was added manganese(IV) oxide (<5 μmparticle size, 85%, 12.39 g, 121 mmol, 8.7 mol equiv) and the mixturewas stirred overnight at room temperature. The mixture was filteredthrough celite and the cake was washed with dichloromethane. The solventwas removed from the filtrate under reduced pressure to give the crudematerial (4.40 g) as a yellow oil. Purification by column chromatographyon silica gel (97:3 CH₂Cl₂:CH₃OH) gave the title compound (3.27 g, 72%).¹H NMR (CDCl₃) δ 1.45 (s, 9H), 4.48-4.63 (m, 4H), 7.16-7.26 (m, 4H),7.65 (td, 1H, J=7.7, 1.5 Hz), 7.83 (d, 2H, 9.0 Hz), 8.53 (d, 1H, J=4.5Hz), 9.99 (s, 1H).

[0135]N-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-guinolinyl)-1,4-benzenedimethanamine

[0136] Using general procedure B: A stirred solution of8-amino-5,6,7,8-tetrahydroquinoline (4.16 g, 28.1 mmol) and4-[[N-(-t-butoxycarbonyl)-N-(2-pyridinylmethyl)amino]methyl]benzylaldehyde(9.15 g, 28.1 mmol) in CH₂Cl₂ (300 mL) was reacted with sodiumtriacetoxyborohydride (8.50 g, 40.1 mmol) overnight. Purification of thecrude product by column chromatography on silica gel (EtOAc) gave thetitle compound (9.65 g, 75%) as a yellow oil. ¹H NMR (CDCl₃) mixture ofrotational isomers δ 1.41 (br s) and 1.48 (br s) (total 9H), 1.76-1.83(m, 2H), 2.02-2.06 (m, 1H), 2.15-2.18 (m, 1H), 2.75-2.83 (m, 2H),3.81-3.85 (m, 1H), 3.86 (d, 1H, J=12 Hz), 3.97 (d, 1H, J=12 Hz), 4.44(br s, 2H), 4.53 (br s, 2H), 7.04 (dd, 1H, J=7.8, 4.8 Hz), 7.12-7.25 (m,4H), 7.33-7.37 (m, 3H), 7.62 (td, 1H, J=7.5, 1.8 Hz), 8.38 (dd, 1H,J=4.8, 1.2 Hz), 8.52 (dd, 1H, J=5.7, 1.8 Hz).

[0137] Preparation ofN-(diethylphosphoryl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-guinolinyl)-1,4-benzenedimethanamine

[0138] Using identical procedures to those described above followingreaction of 4-[[(2-pyridinylmethyl)amino]methyl]benzyl alcohol withdiethyl chlorophosphate gave the title compound. ¹H NMR (CDCl₃) δ 1.29(t, 6H, J=6.3 Hz), 1.72-1.84 (m, 2H), 1.99-2.06 (m, 1H), 2.16-2.22 (m,1H), 2.70-2.89 (m, 2H), 3.84-3.87 (m, 1H), 3.86 (d, 1H, J=12.6 Hz), 3.97(d, 1H, J=12.6 Hz), 4.03-4.15 (m, 4H), 4.17 (d, 2H, J=12 Hz), 4.22 (d,2H, J=12 Hz), 7.06 (dd, 1H, J=7.8, 4.8 Hz), 7.14 (ddd, 1H, J=7.5, 4.8,0.9 Hz), 7.25 (d, 2H, J=7.8 Hz), 7.34 (d, 2H, J=7.8 Hz), 7.36-7.39 (m,2H), 7.63 (td, 1H, J=7.8, 0.9 Hz), 8.38 (dd, 1H, J=4.5, 1.5 Hz), 8.53(br d, 1H, J=4.1 Hz); ¹³C NMR (CDCl₃) δ 15.82 (d, J=7.1 Hz), 19.33,28.23, 28.47, 48.86, 50.05, 51.16, 57.21, 62.11 (d, J=5.3 Hz), 121.47,121.71, 121.97, 127.97 (2 carbons), 128.57 (2 carbons), 132.05, 135.59,136.03, 136.49, 139.39, 146.42, 148.82, 156.97, 157.91. ES-MS m/z 495(M+H). TABLE 1 EXAMPLE 1N-(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H- AMD7490:cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 2N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8- AMD7491quinolinyl)-1,4-benzenedimethanamine EXAMPLE 3N-(2-pyridinylmethyl)-N′-(6,7-dihydro-5H- AMD7492:cyclopenta[b]pyridin-7-yl)-1,4- benzenedimethanamine EXAMPLE 4N-(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-1- AMD8766:naphthalenyl)-1,4-benzenedimethanamine EXAMPLE 5N-(2-pyridinylmethyl)-N′-(1-naphthalenyl)-1,4- AMD8789:benzenedimethanamine EXAMPLE 6N-(2-pyridinylmethyl)-N′-(8-quinolinyl)-1,4- AMD8776:benzenedimethanamine EXAMPLE 7 N-(2-pyridinylmethyl)-N′-[2-[(2- AMD8859:pyridinylmethyl)amino]ethyl]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4- benzene dimethanamine EXAMPLE 8N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2- AMD8867:ylmethyl)amino]ethyl]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzene dimethanamine. EXAMPLE 9N-(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-8- AMD8746:quinolinyl)-1,4-benzenedimethanamine EXAMPLE 10N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2- AMD8835:ylmethyl)amino]ethyl]-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzene dimethanamine EXAMPLE 11N-(2-pyridinylmethyl)-N′-(2-phenyl-5,6,7,8- AMD8833:tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 12N,N′-bis(2-pyridinylmethyl)-N′-(2-phenyl- AMD8825:5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 13N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-5- AMD8869:quinolinyl)-1,4-benzenedimethanamine EXAMPLE 14N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)- AMD8876:N′-(5,6,7,8-tetrahydro-5-quinolinyl)-1,4- benzenedimethanamine EXAMPLE15 N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)- AMD8751:N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE16 N-(2-pyridinylmethyl)-N′-[(2-amino-3- AMD8777:phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 17N-(2-pyridinylmethyl)-N′-(1H-imidazol-4-ylmethyl)- AMD8763:N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE18 N-(2-pyridinylmethyl)-N′-(2-quinolinylmethyl)- AMD8771:N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE19 N-(2-pyridinylmethyl)-N′-(2-(2- AMD8778:naphthoyl)aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 20N-(2-pyridinylmethyl)-N′-[(S)-(2-acetylamino-3- AMD8781:phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 21N-(2-pyridinylmethyl)-N′-[(S)-(2-acetylamino-3- AMD8782:phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 22N-(2-pyridinylmethyl)-N′-[3-((2- AMD8788:naphthalenylmethyl)amino)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 23N-(2-pyridinylmethyl)-N′-[2-(S)- AMD8733pyrollidinylmethyl]-N′-(5,6,7,8-tetrahydro-8- andquinolinyl)-1,4-benzenedimethanamine AMD8734: EXAMPLE 24N-(2-pyridinylmethyl)-N′-[2-(R)- AMD8756:pyrollidinylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 25N-(2-pyridinylmethyl)-N′-[3-pyrazolylmethyl]- AMD8799:N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE26 N-(2-pyridinylmethyl)-N′-[2-pyrrolylmethyl]- AMD8728:N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine. EXAMPLE27 N-(2-pyridinylmethyl)-N′-[2- AMD8836:thiopheneylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 28N-(2-pyridinylmethyl)-N′-[2-thiazolylmethyl]- AMD8841:N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE29 N-(2-pyridinylmethyl)-N′-[2-furanylmethyl]- AMD8821:N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE30 N-(2-pyridinylmethyl)-N′-[2- AMD8742:[(phenylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 31N-(2-pyridinylmethyl)-N′-(2-aminoethyl)-N′- AMD8743:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 32N-(2-pyridinylmethyl)-N′-3-pyrrolidinyl-N′- AMD8753:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 33N-(2-pyridinylmethyl)-N′-4-piperidinyl-N′- AMD8754:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 34N-(2-pyridinylmethyl)-N′-[2- AMD8784: [(phenyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 35N-(2-pyridinylmethyl)-N′-(7-methoxy-1,2,3,4- AMD8759:tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine EXAMPLE 36N-(2-pyridinylmethyl)-N′-(6-methoxy-1,2,3,4- AMD8762:tetrahydro-2-naphthalenyl)-1,4- benzenedimethanamine. EXAMPLE 37N-(2-pyridinylmethyl)-N′-(1-methyl-1,2,3,4- AMD8770:tetrahydro-2-naphthalenyl)-1,4- benzenedimethanamine. EXAMPLE 38N-(2-pyridinylmethyl)-N′-(7-methoxy-3,4- AMD8790:dihydronaphthalenyl)-1-(aminomethyl)-4-benzamide EXAMPLE 39N-(2-pyridinylmethyl)-N′-(6-methoxy-3,4- AMD8805:dihydronaphthalenyl)-1-(aminomethyl)-4-benzamide. EXAMPLE 40N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)- AMD8902:N′-(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine. EXAMPLE 41N-(2-pyridinylmethyl)-N′-(8-hydroxy-1,2,3,4- AMD8863:tetrahydro-2-naphthalenyl)-1,4- benzenedimethanamine. EXAMPLE 42N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)- AMD 8886:N′-(8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine. EXAMPLE 43N-(2-pyridinylmethyl)-N′-(8-Fluoro-1,2,3,4- AMD8889:tetrahydro-2-naphthalenyl)-1,4- benzenedimethanamine. EXAMPLE 44N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)- AMD8895:N′-(8-Fluoro-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine. EXAMPLE 45N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-7- AMD8852:quinolinyl)-1,4-benzenedimethanamine EXAMPLE 46N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)- AMD8858:N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4- benzenedimethanamine EXAMPLE47 N-(2-pyridinylmethyl)-N′-[2-[(2- AMD8785naphthalenylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 48N-(2-pyridinylmethyl)-N′-[2- AMD8820:(isobutylamino)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 49N-(2-pyridinylmethyl)-N′-[2-[(2- AMD8827:pyridinylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 50N-(2-pyridinylmethyl)-N′-[2-[(2- AMD8828:furanylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 51N-(2-pyridinylmethyl)-N′-(2-guanidinoethyl)- AMD8772:N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE52 N-(2-pyridinylmethyl)-N′-[2-[bis-[(2- AMD8861:methoxy)phenylmethyl]amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzene dimethanamine EXAMPLE53 N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-4- AMD8862ylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro- 8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 54 N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-AMD8887: ylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 55N-(2-pyridinylmethyl)-N′-[2- AMD8816:(phenylureido)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 56N-(2-pyridinylmethyl)-N′-[[N″- AMD8737:(n-butyl)carboxamido]methyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 57N-(2-pyridinylmethyl)-N′-(carboxamidomethyl)- AMD8739:N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE58 N-(2-pyridinylmethyl)-N′-[(N″- AMD8752:phenyl)carboxamidomethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 59N-(2-pyridinylmethyl)-N′-(carboxymethyl)-N′- AMD8765:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 60N-(2-pyridinylmethyl)-N′-(phenylmethyl)-N′- AMD8715:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 61N-(2-pyridinylmethyl)-N′-(1H-benzimidazol-2- AMD8907:ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)- 1,4-benzenedimethanamineEXAMPLE 62 N-(2-pyridinylmethyl)-N′-(5,6-dimethyl-1H- AMD8927:benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8- quinolinyl)-1,4-benzenedimethanamine (hydrobromide salt). EXAMPLE 63N-(2-pyridinylmethyl)-N′-(5-nitro-1H- AMD8926:benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine. EXAMPLE 64N-(2-pyridinylmethyl)-N′-[(1H)-5- AMD 8929:azabenzimidazol-2-ylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 65N-(2-pyridinylmethyl)-N-(4-phenyl-1H-imidazol-2- AMD8931:ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine. EXAMPLE 66 N-(2-pyridinylmethyl)-N′-[2-(2-AMD8783: pyridinyl)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 67N-(2-pyridinylmethyl)-N′-(2-benzoxazolyl)-N′- AMD8764:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 68N-(2-pyridinylmethyl)-N′-(trans-2- AMD8780:aminocyclohexyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 69N-(2-pyridinylmethyl)-N′-(2-phenylethyl)-N′- AMD8818:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 70N-(2-pyridinylmethyl)-N′-(3-phenylpropyl)-N′- AMD8829:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 71N-(2-pyridinylmethyl)-N′-(trans-2- AMD8839:aminocyclopentyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 72 N-[[4-[[(2- AMD8726:pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-glycinamide EXAMPLE 73 N-[[4-[[(2-AMD8738: pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-alaninamide EXAMPLE 74N-[[4-[[(2- AMD8749: pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-aspartamide EXAMPLE 75N-[[4-[[(2- AMD8750: pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-pyrazinamide EXAMPLE 76 N-[[4-[[(2-AMD8740: pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-prolinamide EXAMPLE 77N-[[4-[[(2- AMD8741: pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-lysinamide EXAMPLE 78N-[[4-[[(2- AMD8724: pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-benzamide EXAMPLE 79 N-[[4-[[(2-AMD8725: pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-picolinamide EXAMPLE 80N′-Benzyl-N-[[4- AMD8713: [[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-urea. EXAMPLE 81N′-phenyl-N-[[4-[[(2- AMD8712:pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-urea. EXAMPLE 82N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9- AMD8716: yl)-4-[[(2-pyridinylmethyl)amino]methyl]benzamide EXAMPLE 83N-(5,6,7,8-tetrahydro-8-quinolinyl)-4-[[(2- AMD8717:pyridinylmethyl)amino]methyl]benzamide EXAMPLE 84N,N′-bis(2-pyridinylmethyl)-N′-(5,6,7,8- AMD8634:tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 85N,N′-bis(2-pyridinylmethyl)-N′-(6,7,8,9- AMD8774:tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamineEXAMPLE 86 N,N′-bis(2-pyridinylmethyl)-N′-(6,7-dihydro-5H- AMD8775:cyclopenta[b]pyridin-7-yl)-1,4- benzenedimethanamine EXAMPLE 87N,N′-bis(2-pyridinylmethyl)-N′-(1,2,3,4- AMD8819:tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine EXAMPLE 88N,N′-bis(2-pyridinylmethyl)-N′-[(5,6,7,8- AMD8768:tetrahydro-8-quinolinyl)methyl]-1,4- benzenedimethanamine EXAMPLE 89N,N′-bis(2-pyridinylmethyl)-N′[(6,7- AMD8767:dihydro-5H-cyclopenta[b]pyridin-7-yl)methyl]- 1,4-benzenedimethanamineEXAMPLE 90 N-(2-pyridinylmethyl)-N-(2-methoxyethyl)-N′- AMD8838:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 91N-(2-pyridinylmethyl)-N-[2-(4- AMD8871:methoxyphenyl)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 92N,N′-bis(2-pyridinylmethyl)-1,4-(5,6,7,8- AMD8844:tetrahydro-8-quinolinyl)benzenedimethanamine EXAMPLE 95N-[(2,3-dimethoxyphenyl)methyl]-N′-(2- AMD7129:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 96N,N′-bis(2-pyridinylmethyl)-N-[1-(N″- AMD7130:phenyl-N″-methylureido)-4-piperidinyl]-1,3- benzenedimethanamine EXAMPLE97 N,N′-bis(2-pyridinylmethyl)-N-[N″-p- AMD7131:toluenesulfonylphenylalanyl)-4-piperidinyl]-1,3- benzenedimethanamineEXAMPLE 98 N,N′-bis(2-pyridinylmethyl)-N-[1-[3-(2- AMD7136:chlorophenyl)-5-methyl-isoxazol-4-oyl]-4-piperidinyl]1,3-benzenedimethanamine EXAMPLE 99N-[(2-hydroxyphenyl)methyl]-N′-(2- AMD7138:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 100N-[(4-cyanophenyl)methyl]-N′-(2- AMD7140:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 101N-[(4-cyanophenyl)methyl]-N′-(2- AMD7141:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 102N-[(4-acetamidophenyl)methyl]-N′-(2- AMD7142:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 103 N-[(4-phenoxyphenyl)methyl]-N′-(2-AMD7145: pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 104N-[(1-methyl-2-carboxamido)ethyl]-N,N′-bis(2- AMD7147:pyridinylmethyl)-1,3-benzenedimethanamine EXAMPLE 105N-[(4-benzyloxyphenyl)methyl]-N′-(2- AMD7151:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 106N-[(thiophene-2-yl)methyl]-N′-(2- AMD7155:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 107N-[1-(benzyl)-3-pyrrolidinyl]-N,N′-bis(2- AMD7156:pyridinylmethyl)-1,3-benzenedimethanamine. EXAMPLE 108N-[[1-methyl-3-(pyrazol-3-yl)]propyl]- AMD7159:N,N′-bis(2-pyridinylmethyl)-1,3- benzenedimethanamine. EXAMPLE 109N-[1-(phenyl)ethyl]-N,N′-bis(2- AMD7160:pyridinylmethyl)-1,3-benzenedimethanamine. EXAMPLE 110N-[(3,4-methylenedioxyphenyl)methyl]-N′-(2- AMD7164:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 111N-[1-benzyl-3-carboxymethyl-4-piperidinyl]- AMD7166:N,N′-bis(2-pyridinylmethyl)-1,3- benzenedimethanamine. EXAMPLE 112N-[(3,4-methylenedioxyphenyl)methyl]-N′-(2- AMD7167:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 113N-(3-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N- AMD7168:(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine EXAMPLE 114N-[[1-methyl-2-(2-tolyl)carboxamido]ethyl]- AMD7169:N,N′-bis(2-pyridinylmethyl)-1,3- benzenedimethanamine. EXAMPLE 115N-[(1,5-dimethyl-2-phenyl-3-pyrazolinone-4- AMD7171:yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 116N-[(4-propoxyphenyl)methyl]-N′-(2- AMD7172:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 117N-(1-phenyl-3,5-dimethylpyrazolin-4-ylmethyl)-N′- AMD7175:(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 118N-[1H-imidazol-4-ylmethyl]-N,N′-bis(2- AMD7177:pyridinylmethyl)-1,3-benzenedimethanamine. EXAMPLE 119N-[(3-methoxy-4,5-methylenedioxyphenyl)methyl]- AMD7180:N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 120N-[(3-cyanophenyl)methyl]-N′-(2- AMD7182:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 121N-[(3-cyanophenyl)methyl]-N′-(2- AMD7184:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 122N-(5-ethylthiophene-2-ylmethyl)-N′-(2- AMD7185:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 123N-(5-ethylthiophene-2-ylmethyl)-N′-(2- AMD7186:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanam ine EXAMPLE 124N-[(2,6-difluorophenyl)methyl]-N′-(2- AMD7187:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 125N-[(2,6-difluorophenyl)methyl]-N′-(2- AMD7188:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 126N-[(2-difluoromethoxyphenyl)methyl]-N′-(2- AMD7189:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 127N-(2-difluoromethoxyphenylmethyl)-N′-(2- AMD7195:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 128N-(1,4-benzodioxan-6-ylmethyl)-N′-(2- AMD7196:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 129 N,N′-bis(2-pyridinylmethyl)-N-[1-(N″- AMD7197:phenyl-N″-methylureido)-4-piperidinyl]-1,4- benzenedimethanamine.EXAMPLE 130 N, N′-bis(2-pyridinylmethyl)-N-[N″-p- AMD7198:toluenesulfonylphenylalanyl)-4-piperidinyl]-1,4- benzenedimethanamine.EXAMPLE 131 N-[1-(3-pyridinecarboxamido)-4-piperidinyl]- AMD7199:N,N′-bis(2-pyridinylmethyl)-1,4- benzenedimethanamine. EXAMPLE 132N-[1-(cyclopropylcarboxamido)-4-piperidinyl]- AMD7200:N,N′-bis(2-pyridinylmethyl)-1,4- benzenedimethanamine EXAMPLE 133N-[1-(1-phenylcyclopropylcarboxamido)-4- AMD7201:piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4- benzenedimethanamine.EXAMPLE 134 N-(1,4-benzodioxan-6-ylmethyl)-N′-(2- AMD7202:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 135N-[1-[3-(2-chlorophenyl)-5-methyl-isoxazol-4- AMD7203:carboxamido]-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine EXAMPLE 136N-[1-(2-thiomethylpyridine-3-carboxamido)-4- AMD7204:piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4- benzenedimethanamineEXAMPLE 137 N-[(2,4-difluorophenyl)methyl]-N′-(2- AMD7207:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 138N-(1-methylpyrrol-2-ylmethyl)-N′-(2- AMD7208:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 139N-[(2-hydroxyphenyl)methyl]-N′-(2- AMD7209:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 140N-[(3-methoxy-4,5-methylenedioxyphenyl)methyl]- AMD7212:N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 141N-(3-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N- AMD7216:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 142N-[2-(N″-morpholinomethyl)-1-cyclopentyl]- AMD7217:N,N′-bis(2-pyridinylmethyl)-1,4- benzenedimethanamine EXAMPLE 143N-[(1-methyl-3-piperidinyl)propyl]-N,N′- AMD7220:bis(2-pyridinylmethyl)-1,4-benzenedimethanamine EXAMPLE 144N-(1-methylbenzimidazol-2-ylmethyl)-N′-(2- AMD7222:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 145N-[1-(benzyl)-3-pyrrolidinyl]-N,N′-bis(2- AMD7223:pyridinylmethyl)-1,4-benzenedimethanamine EXAMPLE 146N-[[(1-phenyl-3-(N″-morpholino)]propyl]- AMD7228:N,N′-bis(2-pyridinylmethyl)-1,4- benzenedimethanamine EXAMPLE 147N-[1-(iso-propyl)-4-piperidinyl]-N,N′-bis(2- AMD7229:pyridinylmethyl)-1,4-benzenedimethanamine EXAMPLE 148N-[1-(ethoxycarbonyl)-4-piperidinyl]-N′-(2- AMD7230:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 149N-[(1-methyl-3-pyrazolyl)propyl]-N′-(2- AMD7231:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 150 N-[1-methyl-2-(N″,N″- AMD7235:diethylcarboxamido)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine EXAMPLE 151N-[(1-methyl-2-phenylsulfonyl)ethyl]-N′-(2- AMD7236:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 152N-[(2-chloro-4,5-methylenedioxyphenyl)methyl]- AMD7238:N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 153 N-[1-methyl-2-[N″-(4-AMD7239: chlorophenyl)carboxamido]ethyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 154N-(1-acetoxyindol-3-ylmethyl)-N′-(2- AMD7241:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 155N-[(3-benzyloxy-4-methoxyphenyl)methyl]- AMD7242:N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 156N-(3-quinolylmethyl)-N′-(2-pyridinylmethyl)- AMD7244:N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE157 N-[(8-hydroxy)-2-quinolylmethyl]-N′-(2- AMD7245:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 158N-(2-quinolylmethyl)-N′-(2-pyridinylmethyl)- AMD7247:N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine EXAMPLE 159N-[(4-acetamidophenyl)methyl]-N′-(2- AMD7249:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 160N-[1H-imidazol-2-ylmethyl]-N,N′-bis(2- AMD7250:pyridinylmethyl)-1,4-benzenedimethanamine EXAMPLE 161N-(3-quinolylmethyl)-N′-(2-pyridinylmethyl)- AMD7251:N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine EXAMPLE 162N-(2-thiazolylmethyl)-N′-(2-pyridinylmethyl)- AMD7252:N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine EXAMPLE 163N-(4-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N- AMD7253:(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine EXAMPLE 164N-[(5-benzyloxy)benzo[b]pyrrol-3- AMD7254:ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4- benzenedimethanamine EXAMPLE165 N-(1-methylpyrazol-2-ylmethyl)-N′-(2- AMD7256:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine EXAMPLE 166N-[(4-methyl)-1H-imidazol-5-ylmethyl]- AMD7257:N,N′-bis(2-pyridinylmethyl)-1,4- benzenedimethanamine EXAMPLE 167N-[[(4-dimethylamino)-1- AMD7259: napthalenyl]methyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine EXAMPLE 168N-[1,5-dimethyl-2-phenyl-3-pyrazolinone-4- AMD7260:ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4- benzenedimethanamine EXAMPLE169 N-[1-[(1-acetyl-2-(R)-prolinyl]-4- AMD7261:piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine EXAMPLE 170N-[1-[2-acetamidobenzoyl-4-piperidinyl]-4- AMD7262:piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine EXAMPLE 171N-[(2-cyano-2-phenyl)ethyl]-N′-(2- AMD7270:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 172N-[(N″-acetyltryptophanyl)-4-piperidinyl]- AMD7272:N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine EXAMPLE 173N-[(N″-benzoylvalinyl)-4-piperidinyl]-N-[2- AMD7273:(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3- benzenedimethanamineEXAMPLE 174 N-[(4-dimethylaminophenyl)methyl]-N′-(2- AMD7274:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 175N-(4-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N- AMD7275:(5,6,7,8-tetrahydro-8-quinolinyl)-1,4- benzenedimethanamine EXAMPLE 176N-(1-methylbenzimadazol-2-ylmethyl)-N′-(2- AMD7276:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4- benzenedimethanamine EXAMPLE 177N-[1-butyl-4-piperidinyl]-N-[2-(2- AMD7277:pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3- benzenedimethanamineEXAMPLE 178 N-[1-benzoyl-4-piperidinyl]-N-[2-(2- AMD7278:pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3- benzenedimethanamineEXAMPLE 179 N-[1-(benzyl)-3-pyrrolidinyl]-N-[2-(2- AMD7290:pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3- benzenedimethanamineEXAMPLE 180 N-[(1-methyl)benzo[b]pyrrol-3- AMD7309:ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine EXAMPLE 181N-[1H-imidazol-4-ylmethyl]-N-[2-(2- AMD7311:pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3- benzenedimethanamineEXAMPLE 182 N-[1-(benzyl)-4-piperidinyl]-N-[2-(2- AMD7359:pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4- benzenedimethanamineEXAMPLE 183 N-[1-methylbenzimidazol-2-ylmethyl]-N-[2- AMD7374:(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)- 1,4-benzenedimethanamineEXAMPLE 184 N-[(2-phenyl)benzo[b]pyrrol-3-ylmethyl]- AMD7379:N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4-benzenedimethanamine EXAMPLE 185N-[(6-methylpyridin-2-yl)methyl]-N′-(2- AMD9025:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine EXAMPLE 186N-(3-methyl-1H-pyrazol-5-ylmethyl)-N′-(2- AMD9031:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine EXAMPLE 187N-[(2-methoxyphenyl)methyl]-N′-(2- AMD9032:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine EXAMPLE 188N-[(2-ethoxyphenyl)methyl]-N′-(2- AMD9039:pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,3- benzenedimethanamine EXAMPLE 189N-(benzyloxyethyl)-N′-(2-pyridinylmethyl)- AMD9045:N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3- benzenedimethanamine EXAMPLE190 N-[(2-ethoxy-1-naphthalenyl)methyl]-N′-(2- AMD9052:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine EXAMPLE 191N-[(6-methylpyridin-2-yl)methyl]-N′-(2- AMD9053:pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine

[0139] Having now generally described the invention, the same will bemore readily understood through reference to the following exampleswhich are provided by way of illustration, and are not intended to belimiting of the present invention, unless specified.

EXAMPLES Example 1 AMD7490: Preparation ofN-(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine(hydrobromide salt)

[0140] General Procedure C: Deprotection of the 2-nitobenzenesulfonylGroup (nosyl).

[0141] To a stirred solution of the nosyl-protected amine (1 equivalent)in anhydrous CH₃CN (or DMF) (concentration ˜0.05 M), at roomtemperature, was added thiophenol (4-8 equiv.) followed by powderedK₂CO₃ (8-12 equivalents). The resulting bright yellow solution wasstirred at room temperature (or 50° C.) for 1-24 hours. The solvent wasremoved under reduced pressure and CH₂Cl₂ (10 mL/mmol amine) and water(2 mL/mmol amine) were added to the residue. The phases were separatedand the aqueous phase was extracted with CH₂Cl₂ (3×5 mL). The combinedorganic phases were dried (Na₂SO₄) and concentrated. Purification of thecrude material by chromatography provided the free base.

[0142] Alternative work-up: the reaction mixture was filtered andconcentrated to provide a yellow oil which was purified bychromatography on basic alumina (eluant CH₂Cl₂ then 20:1 CH₂Cl₂-CH₃OH)and provided the free base as a colorless oil.

[0143] To a stirred solution of AMD8812 (0.250 g, 0.448 mmol) inanhydrous CH₃CN (9 mL) was added thiophenol (0.16 mL, 1.56 mmol)followed by powdered K₂CO₃ (0.263 g, 1.90 mmol). The reaction mixturewas heated at 50° C. overnight then cooled to room temperature. Themixture was filtered and concentrated to provide a yellow oil which waspurified by column chromatography on basic alumina (CH₂Cl₂ then 20:1CH₂Cl₂-CH₃OH) to give the free base as a colorless oil (0.071 g).

[0144] General Procedure D: Salt Formation Using Saturated HBr(g) inAcetic Acid.

[0145] To a solution of the free base in glacial acetic acid (ordioxane) (2 mL) was added, a saturated solution of HBr(g) in acetic acid(or dioxane) (2 mL). A large volume of ether (25 mL) was then added toprecipitate a solid, which was allowed to settle to the bottom of theflask and the supernatant solution was decanted. The solid was washed bydecantation with ether (3×25 mL) and the remaining traces of solventwere removed under vacuum. For additional purification (wherenecessary), the solid can be dissolved in methanol and re-precipitatedwith a large volume of ether. Washing the solid with ether bydecantation, followed by drying of the solid in vacuo (0.1 Torr) gavethe desired compound.

[0146] Using general procedure D: the free base from above (0.071 g,0.19 mmol) gave AMD7490 (0.135 g). ¹H NMR (D₂O) δ 1.27-1.39 (m, 1H),1.66-2.14 (m, 4H); 2.22-2.31 (m, 1H), 2.82-2.88 (m, 2H), 4.43 (d, 2H,J=4.5 Hz), 4.47 (s, 2H), 4.62 (s, 2H), 4.73 (dd, 1H, J=10.8, 1.5 Hz),7.37 (dd, 1H, J=5.0,7.8 Hz), 7.59 (d, 2H, J=8.3 Hz), 7.65 (d, 2H, J=8.3Hz), 7.73 (dd, 1H, J=1.5, 7.5 Hz), 7.85 (d, 1H, J=7.5 Hz), 7.90 (d, 1H,J=8.4 Hz), 8.35 (td, 1H, J=7.8, 1.0 Hz), 8.45 (dd, 1H, J=1.5, 5.1 Hz),8.37 (dd, 1H, J=1.0, 5.4 Hz); ¹³C NMR (D₂O) δ 26.18, 28.59, 30.21,33.02, 48.82, 50.07, 51.41, 61.52, 124.41, 127.04 (2 carbons), 131.18 (2carbons), 131.25 (2 carbons), 131.88, 133.35, 137.98, 139.70, 144.38,145.59, 146.35, 147.38, 153.76. ES-MS m/z 373 (M+H). Anal. Calcd. forC₂₄H₂₈N₄.4.0HBr.1.2CH₃CO₂H.1.8H₂O: C, 39.60; H, 5.09; N, 7.00; Br,39.92. Found: C, 39.52; H, 5.04; N, 7.02; Br, 40.18.

Example 2 AMD7491: Preparation ofN-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0147] To a stirred solution of 8-amino-5,6,7,8-tetrahydroquinoline(0.233, 1.58 mmol) in CH₂Cl₂ (16 mL) was added triethylamine (0.33 mL,2.37 mmol) followed by 2-nitrobenzenesulfonyl chloride (0.374 g, 1.69mmol). The resultant solution was stirred at room temperature for 24hours then poured into saturated aqueous NaHCO₃ (20 mL). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×20 mL). Thecombined organic extracts were washed with water (2×10 mL), dried(Na₂SO₄), and concentrated. Purification of the crude material by flashchromatography (silica gel (24 g), 30:1 CH₂Cl₂-CH₃OH) provided 0.270 gof a yellow foam.

[0148] The foam from above was dissolved in CH₃CN (16 mL), treated withN-[1-methylene-4-(chloromethylene)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(Bridger et al. WO 00/02870) (0.412 g, 0.89 mmol) and K₂CO₃ (0.279 g,2.02 mmol) and heated to reflux for 22 hours. The mixture was cooled toroom temperature, concentrated, and partitioned between CH₂Cl₂ (30 mL)and water (10 mL). The phases were separated and the aqueous phase wasextracted with CH₂Cl₂ (2×10 mL). The combined organic extracts weredried (Na₂SO₄) and concentrated. Purification of the crude material bycolumn chromatography (silica gel, 30:1 CH₂Cl₂-CH₃OH) provided 0.448 gof a yellow solid.

[0149] The yellow solid was reacted with thiophenol (0.40 mL, 3.90 mmol)and K₂CO₃ (0.628 g, 4.54 mmol) in CH₃CN (11 mL) using general procedureC. The crude product was purified on basic alumina (CH₂Cl₂ followed by20:1 CH₂Cl₂-CH₃OH) followed by radial chromatography on silica gel (1 mmplate, 20:1:1 CHCl₃-CH₃OH-NH₄OH) to provide the free base (0.035 g) as acolorless oil. Conversion to the hydrobromide salt using GeneralProcedure D gave AMD7491 (0.079 g) as a white solid. ¹H NMR (D₂O) δ1.92-2.11 (m, 2H), 2.25-2.47 (m, 2H), 2.93-3.11 (m, 2H), 4.46 (s, 2H),4.47 (d, 1H, J=13.2 Hz), 4.55 (d, 1H, J=13.2 Hz), 4.62 (s, 2H),4.74-4.79 (m, 1H, overlaps with HOD), 7.59-7.69 (m, 5H), 7.81-7.90 (m,2H), 8.05 (d, 1H, J=7.8 Hz), 8.33 (tt, 1H, J=7.8, 1.5 Hz), 8.58 (br d,1H, J=4.5 Hz), 8.77 (br d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 18.01, 24.58,27.18, 48.99, 49.11, 51.35, 55.79, 126.20, 126.91 (2 carbons), 131.26 (2carbons), 131.32 (2 carbons), 132.11, 132.64, 137.53, 143.56, 144.02,145.02, 146.45, 146.56, 147.56. ES-MS m/z 359 (M+H). Anal. Calcd. forC₂₃H₂₆N₄.4.1HBr.1.8H₂O: C, 38.23; H, 4.70; N, 7.75; Br, 45.33. Found: C,38.21; H, 4.63; N, 7.55; Br, 45.50.

Example 3 AMD7492: Preparation ofN-(2-pyridinylmethyl)-N′-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1,4-benzenedimethanamine(hydrobromide salt)

[0150] To a stirred solution of7-amino-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 1.12 mmol) inanhydrous methanol (7 mL), at room temperature, was addedN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(0.30 g, 0.733 mmol) and the solution was stirred at room temperatureovernight. NaBH₃CN (0.137 g, 2.18 mmol) was added to the solution andthe reaction mixture was stirred at room temperature for 24 hours. Thesolvent was removed under reduced pressure and the residue was dissolvedin 1.0 M aqueous NaOH (10 mL). The aqueous solution was extracted withCH₂Cl₂ (3×10 mL) and the combined organic extracts were dried (Na₂SO₄)and concentrated. Purification of the crude material by radialchromatography on silica gel (2 mm plate, 25:1 CH₂Cl₂-CH₃OH) provided0.254 g of the secondary amine as a red oil.

[0151] Using General Procedures C and D: The oil from above was reactedwith thiophenol (0.17 mL, 1.66 mmol) and K₂CO₃ (0.280 g, 2.03 mmol) inCH₃CN (10 mL). The crude material was purified by chromatography onbasic alumina (25 g, eluant CH₂Cl₂ followed by 20:1 CH₂Cl₂-CH₃OH) togive 0.053 g of the free amine as a brown oil. Salt formation gaveAMD7492 (0.124 g) as a white solid. ¹H NMR (D₂O) δ 2.43-2.52 (m, 1H),2.77-2.86 (m, 1H); 3.17 (ddd, 1H, J=17.1, 9.0, 4.8 Hz), 3.31 (dd, 1H,J=17.1, 8.1 Hz), 4.47 (s, 2H), 4.53 (s, 2H), 4.63 (s, 2H), 5.10 (dd, 1H,J=4.5, 8.4 Hz), 7.61 (s, 4H), 7.73 (dd, 1H, J=5.4, 7.8 Hz), 7.84-7.92(m, 2H), 8.21 (d, 1H, J=72 Hz), 8.35 (td, 1H, J=7.8, 1.5 Hz), 8.61 (d,1H, J=5.1 Hz), 8.77 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 27.45, 28.34,48.88, 49.64, 51.37, 61.32, 126.91, 127.01, 127.04, 131.20 (2 carbons),131.35 (2 carbons), 132.11, 132.60, 139.92, 142.65, 144.29, 145.69,146.39, 147.39, 153.21. ES-MS m/z 345 (M+H). Anal. Calcd. forC₂₂H₂₄N₄.3.9HBr.0.2 CH₃CO₂H.1.7H₂O: C, 38.29; H, 4.60; N, 7.97; Br,44.35. Found: C, 38.21; H, 4.62; N, 7.94; Br, 44.44.

Example 4 AMD8766: Preparation ofN-(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0152] General Procedure E: Reductive Amination Via Hydrogenation.

[0153] 1-amino-1,2,3,4-tetrahydronapthalene (0.104 g, 0.70 mmol) wascondensed withN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(t-butyloxycarbonyl)-2-(aminomethyl)pyridine (0.182 g, 0.56 mmol) in methanol (5.5 mL) overnight.Palladium on activated carbon (10%, 48 mg) was added and the mixture washydrogenated (1 atmosphere) at room temperature overnight. The reactionmixture was filtered through celite and the cake was washed withmethanol. The combined filtrates were evaporated under reduced pressureand the residue was purified by radial chromatography on silica gel (2mm plate, 25:1 CH₂Cl₂-CH₃OH) to give a colourless oil (0.100 g).Conversion to the hydrobromide salt using General Procedure D gaveAMD8766 as a white solid (0.099 g). ¹H NMR (D₂O) δ 1.85-1.91 (m, 2H),2.03-2.16 (m, 1H), 2.22-2.31 (m, 1H), 2.78 (ddd, 1H, J=17.4, 7.5, 7.5Hz), 2.90 (ddd, 1H, J=17.4, 5.1, 5.1 Hz), 4.33 (d, 2H, J=4.2 Hz), 4.43(s, 2H), 4.55 (dd, 1H, J=4.5, 4.5 Hz), 4.62 (s, 2H), 7.24-7.37 (m, 4H),7.52-7.58 (m, 4H), 7.84-7.94 (m, 2H), 8.36 (td, 1H, J=7.8, 1.5 Hz), 8.74(br d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 17.92, 25.25, 28.15, 48.45, 48.57,51.41, 56.36, 126.81, 127.20, 127.31, 129.77, 129.92, 129.99, 130.51,131.18 (2 carbons), 131.29 (2 carbons), 131.79, 132.92, 139.33, 144.87,145.87, 146.99. ES-MS m/z 358 (M+H). Anal. Calcd. forC₂₄H₂₇N₃.3.0HBr.0.5H₂O: C, 47.32; H, 5.13; N, 6.90; Br, 39.35. Found: C,47.40; H, 5.04; N, 6.96; Br, 39.25.

Example 5 AMD8789: Preparation ofN-(2-pyridinylmethyl)-N′-(1-naphthalenyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0154] 1-Aminonapthalene (0.100 g, 0.70 mmol) was condensed withN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(t-butyloxycarbonyl)-2-(aminomethyl)pyridine(0.182 g, 0.56 mmol) in methanol (6 mL) overnight and the correspondingimine was reduced with NaBH₄ (0.051 g, 1.35 mmol) (see GeneralProcedures A and B). Purification of the crude material by radialchromatography on silica gel (2 mm plate, 100:1 CH₂Cl₂-CH₃OH) provided0.168 g of a colorless oil.

[0155] The oil was converted to the hydrobromide salt using HBr/aceticacid (General Procedure D) to give a white solid (0.156 g). The solidwas partitioned between CH₂Cl₂ (10 mL) and 10 M aqueous solution of NaOH(5 mL). The phases were separated and the aqueous phase was extractedwith CH₂Cl₂ (3×10 mL). The combined organic extracts were dried (Na₂SO₄)and concentrated. Purification of the residue by radial chromatographyon silica gel (1 mm plate, 100:5:1 CH₂Cl₂-CH₃OH-NH₄OH) gave a colorlessoil (0.04 g). Formation of the hydrobromide salt for a second time usingGeneral Procedure D provided a pure sample of AMD8789 (0.040 g) as awhite solid. ¹H NMR (D₂O) δ 4.32 (s, 2H), 4.41 (s, 2H), 4.79 (s, 2H,overlaps with HOD), 7.25 (d, 2H, J=7.8 Hz), 7.31-7.37 (m, 3H), 7.46 (dd,1H, J=7.8, 7.8 Hz), 7.54-7.66 (m, 2H), 7.74-7.79 (m, 2H), 7.86 (d, 1H,J=8.4 Hz), 7.99 (d, 2H, J=8.1 Hz), 8.26 (t, 1H, J=7.8 Hz), 8.70 (d, 1H,J=5.1 Hz); ¹³C NMR (D₂O) δ 48.95, 50.99, 54.62, 120.39, 125.43, 125.98,126.38, 126.48, 127.66, 129.55, 129.81, 130.90, 131.84, 132.02, 132.19,134.45, 143.07, 147.09, 147.95. ES-MS m/z 354 (M+H). Anal. Calcd. forC₂₄H₂₃N₃.2.9HBr.1.3H₂O: C, 47.14; H, 4.70; N, 6.87; Br, 37.89. Found: C,47.22; H, 4.76; N, 6.63; Br, 37.88.

Example 6 AMD8776: Preparation ofN-(2-pyridinylmethyl)-N′-(8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0156] To a stirred solution of 8-aminoquinoline (0.130 g, 0.902 mmol)in CH₃CN (17 mL) was addedN-[1-methylene-4-(chloromethylene)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(0.364 g, 0.843 mmol) followed by K₂CO₃ (0.237 g, 1.72 mmol) and NaI(0.013 g, 0.084 mmol). The reaction mixture was heated to reflux for 5days then cooled to room temperature. The mixture was concentrated andthe residue was partitioned between CH₂Cl₂ (20 mL) and water (10 mL).The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (3×20 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification of the crude material by radialchromatography on silica gel (2 mm plate, 100:1 CH₂Cl₂-CH₃OH) provided0.205 g of a yellow solid.

[0157] Using General Procedure C: The yellow solid (0.205 g, 0.38 mmol)was reacted with thiophenol (0.20 mL, 1.95 mmol) and K₂CO₃ (0.503 g,3.64 mmol) in CH₃CN (7 mL). Purification of the crude product by radialchromatography on silica gel (2 mm plate, 200:10:2 CH₂Cl₂-CH₃OH-NH₄OH)gave the free base as a yellow oil (0.107 g). Conversion to thehydrobromide salt using General Procedure D gave the crude product,which was re-precipitated from methanol/ether and dried in vacuo to giveAMD8776 as a red-orange solid (0.153 g). ¹H NMR (D₂O) δ 4.37 (s, 2H),4.55 (s, 2H), 4.64 (s, 2H), 7.20 (d, 1H, J=7.2 Hz), 7.42-7.64 (m, 6H),7.77-7.93 (m, 3H), 8.26-8.33 (m, 1H), 8.69 (d, 1H, J=4.8 Hz), 8.88 (d,1H, J=8.4 Hz), 8.92 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 48.11, 48.53,51.49, 116.37, 119.53, 121.98, 126.95, 127.06, 129.09 (2 carbons),129.76, 130.41, 130.52, 130.53, 130.83 (2 carbons), 137.79, 139.52,143.60, 144.40, 146.09, 146.90, 147.30. ES-MS m/z 355 (M+H). Anal.Calcd. for C₂₃H₂₂N₄.3.0HBr.0.9H₂O: C, 45.04; H, 4.40; N, 9.13; Br,39.08. Found: C, 45.14; H, 4.22; N, 9.06; Br, 38.86.

Example 7 AMD8859: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(2-pyridinylmethyl)amino]ethyl]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine

[0158] Preparation of 8-amino-1,2,3,4-tetrahydroquinoline.

[0159] A mixture of 8-nitroquinoline (1.035 g, 5,94 mmol) and platinumoxide (35 mg, 0.15 mmol, 2.5 mol %) in glacial acetic acid washydrogenated (20 psi) on a Parr Shaker at room temperature for 20 hours.The mixture was filtered through celite and the cake was washed withmethanol. The solvent was removed from the filtrate to afford a red oil.The oil was dissolved in a mixture of CH₂Cl₂ (25 mL) and saturatedaqueous NaHCO₃ (10 mL) and a 10 M aqueous solution of sodium hydroxidewas added dropwise until the aqueous phase was basic (pH ˜14) to litmuspaper. The phases were separated and the aqueous phase was extractedwith CH₂Cl₂ (3×10 mL). The combined organic extracts were washed oncewith water (10 mL), dried (Na₂SO₄), and concentrated. The residue wasfiltered (100:1 CH₂Cl₂-CH₃OH) through a short pad of silica gel (30 g)and afforded 0.699 g (79%) of 8-amino-1,2,3,4-tetrahydroquinoline as anoil. ¹H NMR (CDCl₃) δ 1.89-1.97 (m, 2H), 2.79 (t, 2H, J=6.3 Hz), 3.34(t, 2H, J=5.4 Hz), 3.20-3.60 (br signal, 3H, NH & NH), 6.55-6.64 (m,3H); ¹³C NMR (CDCl₃) δ 22.79, 27.44, 42.98, 114.50, 118.47, 121.56,123.70, 134.24 (2 carbons).

[0160] 8-(tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline.

[0161] To a stirred solution of 8-amino-1,2,3,4-tetrahydroquinoline(0.530 g, 3.58 mmol) in THF (30 mL) and water (3 mL), at roomtemperature, was added di-tert-butyl dicarbonate (0.782 g, 3.58 mmol).After 5 hours, the mixture was poured into water (10 mL) and dilutedwith ethyl acetate (50 mL). The phases were separated and the aqueousphase was extracted with ethyl acetate (3×10 mL). The combined organicextracts were dried (MgSO₄) and concentrated. Purification of the crudematerial by radial chromatography (4 mm plate, 5:1 hexanes-ethylacetate) provided 0.650 g (73%) of8-(-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline as a whitesolid. ¹H NMR (CDCl₃) δ 1.51 (s, 9H), 1.86-1.94 (m, 2H), 2.78 (t, 2H,J=6.3 Hz), 3.32 (t, 2H, J=5.4 Hz), 3.88 (br s, 1H, NH), 6.01 (br s, 1H,NH), 6.64 (dd, 1H, J=7.8, 7.2 Hz), 6.82 (d, 1H, J=7.2 Hz), 7.13 (d, 1H,J=7.8 Hz); ¹³C NMR (CDCl₃) δ 21.97, 27.20, 28.34 (3 carbons), 42.20,80.36, 117.25, 122.37, 123.65, 126.55 (2 carbons), 138.38, 154.08. ES-MSm/z 271 (M+Na).

[0162]1-Methyl-8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline

[0163] To a stirred solution of8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline (0.876 g,3.52 mmol) in CH₂Cl₂ (35 mL), at room temperature was added excessmethyl iodide (2 mL, 32.12 mmol). The mixture was stirred at roomtemperature for 48 hours. The mixture was poured into saturated aqueousNaHCO₃ (25 mL) and diluted with CH₂Cl₂ (25 mL). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×25 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by flash chromatography (36 g silicagel, 10:1 hexanes-ethyl acetate) provided 0.83 g (90%) of1-methyl-8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline as acolorless oil. ¹H NMR (CDCl₃) δ 1.53 (s, 9H), 1.84-1.92 (m, 2H), 2.62(s, 3H), 2.79 (t, 2H, J=6.6 Hz), 3.03-3.07 (m, 2H), 6.73 (d, 1H, J=7.8Hz), 6.95 (dd, 1H, J=7.8, 7.8 Hz), 7.18 (br s, 1H, NH), 7.82 (br d, 1H,J=7.8 Hz).

[0164] 1-Methyl-8-amino-1,2,3,4-tetrahydroquinoline

[0165] Anhydrous HCl (gas) was bubbled through a stirred solution of1-methyl-8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline(0.83 g, 3.16 mmol) in methanol (30 mL), at room temperature, for 10minutes. The resultant solution was stirred at room temperature for 1hour then concentrated under reduced pressure. The residue waspartitioned between CH₂Cl₂ (50 mL) and aqueous NaOH (10 N, 10 mL). Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(3×10 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated to afford 0.468 g (88%) of1-methyl-8-amino-1,2,3,4-tetrahydroquinoline as a white solid. ¹H NMR(CDCl₃) δ 1.83-1.91 (m, 2H), 2.69 (s, 3H), 2.78 (t, 2H, J=6.6 Hz),3.07-3.11 (m, 2H), 3.84 (br s, 2H, NH₂ ), 6.52 (d, 1H, J=7.5 Hz), 6.56(d, 1H, J=7.5 Hz), 6.81 (dd, 1H, J=7.5, 7.5 Hz).

[0166] Preparation ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine

[0167] Using general procedure B: Reaction of1-methyl-8-amino-1,2,3,4-tetrahydroquinoline (0.451 g, 2.78 mmol) andN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(1.268 g, 3.08 mmol) with NaBH(OAc)₃ (0.896 g, 4.23 mmol) in CH₂Cl₂ (28mL) for 3.5 hours followed by purification of the crude material byflash chromatography (36 g silica gel, 1:2 hexanes-ethyl acetate)provided 1.44 g (93%) of the title compound as an orange solid. ¹H NMR(CDCl₃) δ 1.84-1.93 (m, 2H), 2.68 (s, 3H), 2.79 (t, 2H, J=6.6 Hz),3.06-3.09 (m, 2H), 4.27 (s, 2H), 4.59 (s, 2H), 4.62 (s, 2H), 4.73 (t,1H, J=4.8 Hz), 6.35 (d, 1H, J=7.8 Hz), 6.48 (d, 1H, J=7.5 Hz), 6.85 (dd,1H, J=7.8, 7.5 Hz), 7.09-7.14 (m, 3H), 7.23-7.26 (m, 3H), 7.52-7.57 (m,2H), 7.61-7.68 (m, 2H), 7.95 (d, 1H, J=7.8 Hz), 8.42 (d, 1H, J=4.5 Hz).

[0168]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-[2-(aminoethyl)]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine.

[0169] Using General Procedure B: The solid from above (0.724 g, 1.30mmol) was reacted with N-tert-butoxycarbonyl-2-amino-acetaldehyde (0.484g, 3.04 mmol), NaBH(OAc)₃ (0.633 g, 2.99 mmol), glacial acetic acid(0.17 mL, 2.97 mmol) in CH₂Cl₂ (13 mL) for 21 hours. Purification of thecrude material by radial chromatography on silica gel (4 mm plate, 1:1hexanes-ethyl acetate) provided 0.91 g of a yellow oil. The oil wasdissolved in CH₂Cl₂ (1 mL) and treated with trifluoroacetic acid (1 mL).The resultant solution was stirred at room temperature for 3 hours thenconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂(20 mL) and saturated aqueous NaHCO₃ (20 mL) and the aqueous phase wasmade basic (pH 14) using 10 M aqueous NaOH (˜2 mL). The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×20 mL). Thecombined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by radial chromatography on silicagel (2 mm plate, 20:1 CH₂Cl₂-MeOH containing 1% NH₄OH) provided thetitle compound (0.469 g, 60% for two steps) as a yellow solid. ¹H NMR(CDCl₃) δ 1.44 (br s, 2H, NH₂ ), 1.79-1.87 (m, 2H), 2.73 (t, 2H, J=6.3Hz), 2.79 (t, 2H, J=6.3 Hz), 2.96 (s, 3H), 3.01 (t, 2H, J=6.3 Hz),3.10-3.14 (m, 2H), 4.27 (s, 2H), 4.56 (s, 2H), 4.59 (s, 2H), 6.70-6.78(m, 3H), 7.06-7.12 (m, 5H), 7.20 (d, 1H, J=7.8 Hz), 7.50-7.56 (m, 2H),7.61-7.68 (m, 2H), 7.95 (d, 1H, J=7.8 Hz), 8.41 (d, 1H, J=4.8 Hz).

[0170]N-(2-pyridinylmethyl)-N′-[2-[(2-pyridinylmethyl)amino]ethyl]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(AMD8859).

[0171] Using General Procedure B: The solid from above (0.216 g, 0.36mmol), pyridine-2-carboxaldehyde (30 μL, 0.32 mmol), and NaBH(OAc)₃(0.119 g, 0.56 mmol), were reacted in CH₂Cl₂ (7 mL) for 3 hours.Purification of the crude material by radial chromatography on silicagel (2 mm plate, 20:1 CH₂Cl₂-CH₃OH containing 2% NH₄OH) provided 0.215 gof a yellow oil. Using General Procedure C, the title compound wasobtained by reaction of the oil from above (0.215 g, 0.31 mmol) withthiophenol (0.20 mL, 1.95 mmol) and K₂CO₃ (0.555 g, 4.02 mmol) in CH₃CN(6 mL). Purification of the crude material by radial chromatography onsilica gel (2 mm plate, 40:2:1 CH₂Cl₂-CH₃OH-NH₄OH) gave AMD8859 (0.120g, 68%) as a colorless oil. ¹H NMR (CDCl₃) δ 1.76-1.84 (m, 2H), 2.74 (t,2H, J=6.6 Hz), 2.78 (t, 2H, J=6.6 Hz), 2.96 (s, 3H), 3.07-3.11 (m, 2H),3.19 (t, 2H, J=6.5 Hz), 3.81 (s, 4H), 3.92 (s, 2H), 4.30 (s, 2H),6.70-6.79 (m, 4H), 7.10-7.33 (m, 7H), 7.57-7.67 (m, 2H), 8.52 (br d, 1H,J=4.2 Hz), 8.56 (br d, 1H, J=4.2 Hz); ¹³C NMR (CDCl₃) δ 18.33, 28.96,41.63, 46.94, 49.79, 52.67, 53.69, 54.98, 55.46, 56.43, 119.54, 121.08,122.21, 122.23, 122.41, 122.76, 124.50, 128.43 (2 carbons), 129.50 (2carbons), 129.96, 136.77, 136.83, 138.03, 138.98, 142.91, 143.19,149.59, 149.70, 160.22, 160.29. ES-MS m/z 507 (M+H).

Example 8 AMD8867: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-ylmethyl)amino]ethyl]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine

[0172] Reaction ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-[2-(aminoethyl)]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.140 g, 0.23 mmol) with imidazole-2-carboxaldehyde (0.023 g, 0.24mmol) in CH₂Cl₂ (7 mL) overnight, followed by reduction of thecorresponding imine with NaBH₄ (0.039 g, 1.02 mmol) in CH₂Cl₂ andpurification of the crude material by radial chromatography silica gel(2 mm plate, 40:2:1 CH₂Cl₂-CH₃OH-NH₄OH) provided 0.108 g of a yellowsolid. Using General Procedure C: the free base of the title compoundwas obtained by reaction of the solid from above (0.108 g, 0.16 mmol)with thiophenol (0.10 mL, 0.97 mmol) and K₂CO₃ (0.223 g, 1.61 mmol) inCH₃CN (4 mL). Purification of the crude product by radial chromatographyon silica gel (2 mm plate, 10:1:1 CH₂Cl₂-CH₃OH-NH₄OH) gave AMD8867(0.072 g, 64%) as a colorless oil. ¹H NMR (CDCl₃) δ 1.76-1.83 (m, 2H),1.90-2.50 (br s 2H, NH), 2.61 (t, 2H, J=6.3 Hz), 2.77 (t, 2H, J=6.3 Hz),2.93 (s, 3H), 3.03-3.07 9 m, 2H), 3.14 (t, 2H, J=5.7 Hz), 3.72 (s, 2H),3.81 (s, 2H), 3.93 (s, 2H), 4.26 (s, 2H), 6.74-6.87 (m, 5H), 7.14-7.34(m, 6H), 7.64 (td, 1H, J=7.8, 1.5 Hz), 8.55 (br d, 1H, J=4.5 Hz),9.54-10.06 (br s, 1H, NH). ¹³C NMR (CDCl₃) δ 18.13, 28.86, 41.83, 47.04,47.28, 49.65, 52.58, 53.65, 54.95, 57.19, 119.79, 121.38, 122.40 (2carbons), 122.79 (2 carbons), 124.87, 128.59 (2 carbons), 129.50 (2carbons), 130.22, 136.90, 137.99, 139.16, 143.23, 143.55, 147.70,149.68, 160.11. ES-MS m/z 496 (M+H). Anal. Calcd. for C₃₀H₃₇N₇.0.7H₂O:C, 70.89; H, 7.61; N, 19.29. Found: C, 71.09; H, 7.64; N, 19.39.

Example 9 AMD8746: Preparation ofN-(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0173] A stirred solution of 8-amino-1,2,3,4-tetrahydroquinoline (0.136g, 0.92 mmol) andN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(0.370 g, 0.90 mmol) in benzene (20 mL) was heated to reflux underDean-Stark conditions for 24 hours. The mixture was concentrated,dissolved in MeOH (10 mL) and THF (2 mL) and treated with NaBH₃CN (0.094g, 1.49 mmol) for 72 hours. The mixture was concentrated and partitionedbetween CH₂Cl₂ (20 mL) and a 1.0 M aqueous solution of NaOH (5 mL). Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(3×10 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification of the crude material by flash chromatography(24 g silica gel, 20:1 CH₂Cl₂-CH₃OH) gave the desired product (0.137 g).

[0174] Using General Procedures C and D: The intermediate from above(0.137 g, 0.252 mmol) was reacted with thiophenol (0.18 mL, 1.75 mmol)and K₂CO₃ (0.361 g, 2.61 mmol) in CH₃CN (5 mL). Purification of thecrude product by radial chromatography on silica gel (2 mm plate, 15:1CH₂Cl₂-CH₃OH) gave the free base of the title compound as a yellow oil(0.065 g). Conversion to the hydrobromide salt gave AMD8746 as a whitesolid (0.129 g). ¹H NMR (D₂O) δ 2.07-2.11 (m, 2H), 2.89 (t, 2H, J=6.0Hz), 3.58 (dd, 2H, J=5.4, 5.4 Hz), 4.43 (s, 2H), 4.52 (s, 2H), 4.65 (s,2H), 6.62 (d, 1H, J=8.1 Hz), 6.74 (d, 1H, J=8.1 Hz), 7.13 (t, 1H, J=8.1Hz), 7.48 (s, 4H), 7.89-7.98 (m, 2H), 8.43 (br t, 1H, J=7.8 Hz), 8.77(d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 19.43, 25.51, 43.70, 47.32, 48.13,51.70, 112.57, 118.77, 120.65, 127.42, 127.63, 128.70 (2 carbons),128.94, 129.36, 130.82 (2 carbons), 132.98, 139.89, 140.77, 145.37,145.58, 146.71. ES-MS m/z 359 (M+H). Anal. Calcd. forC₂₃H₂₆N₄.3.6HBr.0.8CH₃CO₂H.2.1H₂O: C, 40.17; H, 5.07; N, 7.62; Br,39.10. Found: C, 40.26; H, 4.71; N, 7.76; Br, 38.91.

Example 10 AMD8835: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-ylmethyl)amino]ethyl]-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine (hydrobromide salt)

[0175] 1-Amino-1,2,3,4-tetrahydronapthalene (0.154 g, 1.05 mmol) wascondensed with imidazole-2-carboxaldehyde (0.103 g, 1.07 mmol) inmethanol (10 mL) overnight. The resulting imine was then hydrogenated(30 psi, room temperature) over Pd/C (10%, 34 mg) overnight. The mixturewas filtered through celite and the cake was washed with methanol. Thecombined filtrates were evaporated under reduced pressure and theresidue was purified by radial chromatography on silica gel (2 mm plate,20:1 CH₂Cl₂-CH₃OH containing 1% NH₄OH) to give a colorless oil (0.202g).

[0176] The oil was reacted withN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(0.368 g, 0.89 mmol) and NaBH₃CN (0.137 g, 2.18 mmol) in methanol (9 mL)with stirring at room temperature for 24 hours. The mixture wasconcentrated and partitioned between CH₂Cl₂ (30 mL) and water (10 mL).The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (3×10 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification of the crude material by radialchromatography on silica gel (2 mm plate, 25:1 CH₂Cl₂-CH₃OH) provided0.365 g of a white solid.

[0177] Using General procedures C and D: The solid from above (0.345 g,0.55 mmol) was treated with thiophenol (0.35 mL, 3.41 mmol) and K₂CO₃(0.773 g, 5.59 mmol) in CH₃CN (11 mL). The crude product was purified byradial chromatography on silica gel (2 mm plate, 100:4:1CH₂Cl₂-CH₃OH-NH₄OH) to give the free base of the title compound as ayellow solid (0.096 g). Conversion to the hydrobromide salt gave AMD8835as a white solid (0.128 g). ¹H NMR (D₂O) δ 1.51-1.62 (m, 1H), 1.90-2.04(m, 2H), 2.20-2.25 (m, 1H), 2.66-2.80 (m, 2H), 3.98 (s, 2H), 4.21 (d,1H, J=12.6 Hz), 4.31-4.44 (m, 4H), 4.56 (s, 2H), 7.14-7.30 (m, 5H), 7.40(s, 4H), 7.75 (br d, 1H, J=7.5 Hz), 7.81 (br d, 1H, J=6.6 Hz), 7.87 (brd, 1H, J=7.8 Hz), 8.32 (br t, 1H, J=7.8 Hz), 8.70 (br d, 1H, J=5.4 Hz);¹³C NMR (D₂O) δ 21.48, 22.23, 29.43, 46.15, 48.45, 51.43, 55.95, 62.17,119.74, 126.94, 127.10, 127.25, 128.37, 128.73, 130.00, 130.20, 130.55,130.83, 140.64, 144.79, 145.81, 147.03. ES-MS m/z 438 (M+H). Anal.Calcd. for C₂₈H₃₁N₅.4.1HBr.2.4H₂O: C, 41.39; H, 4.95; N, 8.62; Br,40.32. Found: C, 41.14; H, 4.62; N, 9.01; Br, 40.32.

[0178] Preparation of 8-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinoline(AMD8786)

[0179] To a vigorously stirred solution of 2-phenylquinoline (6.0 g, 29mmol) in TFA (30 mL) in a 250 mL round-bottomed flask under nitrogen wasadded PtO₂ (332 mg, 1.5 mmol) in one portion. The resulting mixture wasthen placed under a hydrogen atmosphere (H₂ flush for 5 min, then H₂balloon with a wide-bore needle) and heated to 60° C. Stirring wascontinued for 5 h, at which time GLC analysis indicated all of thestarting material was consumed. The reaction was cooled to roomtemperature and the TFA was evaporated in vacuo. The residue wasrendered basic with a minimum amount of 4 N NaOH and extracted withCHCl₃ (3×50 mL), dried (MgSO₄) and concentrated in vacuo. Purificationof the residue by flash chromatography (silica gel, hexane/EtOAc 10:1)afforded 4.85 g of 2-phenyl-5,6,7,8-tetrahydroquinoline (80% yield).

[0180] To a stirred solution of 2-phenyl-5,6,7,8-tetrahydroquinoline(3.80 g, 18 mmol) in glacial acetic acid (10 mL) was added a 30 wt. %aqueous solution of H₂O₂ (2 mL) and the resulting mixture was stirred at70° for 18 h; at this point, another portion of H₂O₂ solution (2 mL) wasadded and stirring was continued for 2 days. The solution was cooled toroom temperature and Na₂CO₃ (10 g) and CHCl₃ (20 mL) were added. Theresulting mixture was allowed to sit 15 min then filtered and theaqueous phase was extracted with CHCl₃ (3×20 mL); the organic fractionswere then combined, dried (MgSO₄) and concentrated. The residue was thentaken up in acetic anhydride (20 mL) and heated at 90° C. for 4 h withstirring. Removal of the Ac₂O under reduced pressure afforded a paleyellow oil which was taken up in methanol (30 mL) and treated with K₂CO₃(100 mg, 0.72 mmol). The resulting mixture was stirred overnight. Asolution of 4 N NaOH (10 mL) was added and the mixture was extractedwith CHCl₃ (3×20 mL), dried (MgSO₄) and concentrated in vacuo.Purification of the crude product by column chromatography (silica gel,hexane/EtOAc 4:1) afforded 3.0 g of8-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinoline AMD 8786 (74% yield) as awhite solid. ¹H NMR (CDCl₃) δ 1.78-1.81 (m, 2H), 1.97-2.02 (m, 1H),2.31-2.33 (m, 1H), 2.76-2.79 (m, 2H), 4.43 (s, 1H), 4.71 (t, 1H, J=7Hz), 7.37-7.46 (m, 4H), 7.52 (d, 1H, J=8 Hz), 7.96 (dd, 2H, J=9, 2 Hz);¹³C NMR (CDCl₃) δ 19.4, 27.8, 30.5, 69.0, 119.0, 126.5, 128.5, 128.7,129.8, 137.6, 138.7, 154.0, 157.5. ES-MS m/z 226 (M+H).

[0181] Preparation of 8-amino-2-phenyl-5,6,7,8-tetrahydroquinoline(AMD8787).

[0182] To a stirred solution of8-hydroxy-2-phenyl-5,6,7,8-tetrahydroquinoline (3.0 g, 13 mmol) inCH₂Cl₂ (25 mL) at 0° C. and triethylamine (4.0 mL, 29 mmol) was addeddropwise, methanesulfonyl chloride (1.6 mL, 21 mmol). The reactionmixture was stirred overnight, then saturated aqueous NaHCO₃ (20 mL) wasadded and the resulting mixture was extracted with CHCl₃ (3×20 mL),dried (MgSO₄) and concentrated in vacuo. The residue was taken up in DMF(20 mL), then sodium azide (1.7 g, 26 mmol) was added and the mixturewas stirred at 60° C. for 5 h. At this time, the mixture was cooled toroom temperature, diluted with aqueous brine solution (20 mL) and theresulting mixture was extracted with diethyl ether (3×20 mL). Theorganic fractions were combined then washed with water (20 mL) and brine(20 mL) then dried (MgSO₄) and concentrated in vacuo. The residue wasdissolved in MeOH/EtOAc 1:1 (20 mL) and placed in a hydrogenation flaskwhich was flushed with nitrogen. Palladium on carbon (10%, 220 mg) wasadded and the mixture was shaken in a Parr hydrogenator under 45 psi ofhydrogen for 8 h. The reaction was filtered through celite and the cakewas washed with CHCl₃ (50 mL). Evaporation of the combined filtratesafforded 8-amino-2-phenyl-5,6,7,8-tetrahydroquinoline (AMD8787) (2.2 g,74%) as a pale yellow oil. ¹H NMR (CD₃OD) δ 1.77-1.87 (m, 2H), 2.00-2.05(m, 1H), 2.36-2.40 (m, 1H), 2.74-2.85 (m, 2H), 4.30 (dd, 1H, J=9, 5 Hz),7.31-7.46 (m, 3H), 7.55 (d, 1H, J=8 Hz), 7.69 (d, 1H, J=8 Hz), 8.11 (d,2H, J=8 Hz); ¹³C NMR (CD₃OD) δ 18.5, 21.1, 24.0, 52.3, 120.7, 127.7,129.7, 130.1, 132.3, 139.6, 153.5, 155.7. ES-MS m/z 225 (M+H). Thisintermediate was used without further purification.

Example 11 AMD8833: Preparation ofN-(2-pyridinylmethyl)-N′-(2-phenyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0183]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(2-phenyl-5,6,7,8-tetrahydro-8-guinolinyl)-1,4-benzenedimethanamine

[0184] Using General Procedure B:

[0185] Reaction of 8-amino-2-phenyl-5,6,7,8-tetrahydroquinoline (100 mg,0.45 mmol) andN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(183 mg, 0.47 mmol) in the presence of NaBH(OAc)₃ (189 mg, 0.90 mmol) inMeOH (3 mL) for 3 hours, followed by purification of the crude productby column chromatography (silica gel, CH₂Cl₂/MeOH/NH₄OH 40:2:1) gave thetitle compound (249 mg, 90%) as a yellow/green foam.

[0186] Using General Procedures C and D: The foam from above (249 mg,0.40 mmol) was reacted with thiophenol (103 μL, 1.0 mmol) and K₂CO₃ (167mg, 1.2 mmol) in DMF (3 mL). The crude product was purified by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH 20:1:1) togive the free base of AMD8833 (103 mg, 59%). Conversion to thehydrobromide salt gave AMD8833 (121 mg, 57%) as a white solid. ¹H NMR(CDCl₃) δ 1.77-1.84 (m, 2H), 2.00-2.07 (m, 1H), 2.25-2.29 (m, 1H),2.77-2.81 (m, 2H), 2.96 (br s, 2H), 3.80-3.96 (m, 5H), 4.05 (d, 1H, J=14Hz), 7.12-7.14 (m, 1H), 7.33-7.50 (m, 10H), 7.63 (t, 1H, J=8 Hz), 7.98(d, 2H, J=7 Hz), 8.54 (br d, 1H, J=5 Hz); ¹³C NMR (CDCl₃) δ 20.0, 28.5,28.8, 51.1, 53.1, 54.3, 57.2, 118.3, 121.8, 122.2, 126.5, 128.1, 128.2,128.5, 130.8, 136.2, 137.5, 138.4, 139.2, 149.1, 154.0, 156.8, 159.5.ES-MS m/z 435 (M+H). Anal. Calcd. for C₂₉H₃₀N₄.3.5HBr.0.2H₂O.0.7C₂H₄O₂:C, 47.94; H, 4.86; N, 7.34; Br, 36.35. Found: C, 47.95; H, 4.91; N,7.32; Br, 36.35.

Example 12 AMD8825: Preparation ofN,N′-bis(2-pyridinylmethyl)-N′-(2-phenyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0187] Using General Procedure A:

[0188] 8-Amino-2-phenyl-5,6,7,8-tetrahydroquinoline (150 mg, 0.67 mmol),pyridine-2-carboxaldehyde (64 μL, 0.67 mmol) and NaBH₃CN (84 mg, 1.3mmol) were reacted in MeOH (3 mL) for 18 h. The crude material isolatedfrom this reaction (180 mg, 85%) was used without further purification.

[0189] The intermediate from above (246 mg, 0.54 mmol) was dissolved inCH₃CN (11 mL).N-[1-methylene-4-(chloromethylene)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(246 mg, 0.54 mmol) was added, followed by K₂CO₃ (158 mg, 1.1 mmol) andthe reaction mixture was heated at 82° C. for two days. Standard work-upand extraction of the crude gum with diethyl ether (3×30 mL), gave thedesired N-alkylated intermediate (305 mg, 74% yield).

[0190] Using General Procedures C and D: The intermediate from above(300 mg, 0.42 mmol) was reacted with thiophenol (108 μL, 1.1 mmol) andK₂CO₃ (174 mg, 1.3 mmol) in DMF (3 mL). Purification of the crudeproduct by column chromatography on silica gel (CHCl₃/MeOH/NH₄OH 40:2:1)afforded the free base of AMD8825 as a colourless oil (62 mg, 30%).Conversion to the hydrobromide salt gave AMD8825 (90 mg, 79% yield) as awhite solid. ¹H NMR (CDCl₃) δ 1.62-1.67 (m, 1H), 1.90-2.00 (m, 2H),2.21-2.25 (m, 1H), 2.64-2.78 (m, 3H), 3.80 (s, 2H), 3.85-3.94 (m, 4H),4.09-4.17 (m, 2H), 4.28 (d, 1H, J=14 Hz), 7.03-7.06 (m, 1H), 7.13-7.15(m, 1H), 7.26-7.30 (m, 3H), 7.37 (d, 1H, J=8 Hz), 7.43 (d, 1H, J=8 Hz),7.49-7.65 (m, 7H), 7.98 (d, 1H, J=8 Hz), 8.18 (d, 2H, J=7 Hz), 8.43 (d,1H, J=4 Hz), 8.54 (d, 1H, J=4 Hz); ¹³C NMR (CDCl₃) δ 21.9, 27.6, 29.0,53.1, 54.3, 55.9, 57.2, 59.1, 117.7, 121.4, 121.8, 122.2, 122.5, 126.6,128.0, 128.4, 128.5, 128.7, 132.6, 136.2, 136.3, 137.1, 138.2, 139.6,148.4, 149.1, 154.1, 158.1, 159.5, 161.9. ES-MS m/z 526 (M+H). Anal.Calcd. for C₃₅H₂₅N₅.4.4HBr.1.6H₂O.1.0C₂H₄O₂: C, 45.79; H, 4.84; N, 7.22;Br, 36.56. Found: C, 45.67; H, 4.86; N, 7.20; Br, 36.22.

[0191] Preparation of 7-amino-5,6,7,8-tetrahydroquinoline (AMD8850) and5-amino-5,6,7,8-tetrahydroquinoline (AMD8851).

[0192] Following the procedure described by Filippi, J. (Bull. Soc.Chim. Fr. 1968, 1, 259-67).

[0193] The Skraup reaction of m-nitroaniline and glycerol in thepresence of As₂O₃ and H₂SO₄ afforded a 65:35 mixture of 5-nitroquinolineand 7-nitroquinoline, respectively, in a combined yield of 21%. Thismixture (6.6 g, 38 mmol) was taken up in EtOAc (50 mL), placed in a 250mL round-bottom flask, and flushed with nitrogen. Next, 10% Pd/C (0.6 g)was added and the mixture was placed under a hydrogen atmosphere (H₂balloon) and stirred vigorously for 18 h. The residue was filteredthrough a pad of celite, eluting with CHCl₃ (100 mL), and the solventwas removed in vacuo to afford 5.0 g of a 65:35 mixture of5-aminoquinoline and 7-aminoquinoline, respectively (91% yield). Thismaterial was taken up in CH₂Cl₂ (100 mL) and pyridine (3 mL, 37 mmol)and DMAP (100 mg, 0.82 mmol) followed by Ac₂O (5 mL, 53 mmol) wereadded. Stirring was continued for 1 h, at which point 4 N NaOH (50 mL)was added and the mixture was extracted with CH₂Cl₂ (3×50 mL). Thecombined organic fractions were dried (MgSO₄) and concentrated in vacuoto give 6.5 g of a mixture of N-acetylated products (quant. yield).

[0194] To a vigorously stirred solution of 5-(N-acetylamino)-quinolineand 7-(N-acetylamino)-quinoline (2.7 g, 14 mmol) in TFA (30 mL) in a 250mL round-bottom flask under nitrogen was added PtO₂ (165 mg, 0.72 mmol).The flask was then flushed with H₂ for 5 min, then placed under a H₂atmosphere (H₂ balloon) and heated to 60° C. for 18 hours. The reactionmixture was cooled to room temperature and the solvent was evaporated.The residue was rendered basic with a minimum volume of 4 N NaOH andextracted with CHCl₃ (3×50 mL), and the combined extracts were dried(MgSO₄) and concentrated in vacuo. Purification of the residue by columnchromatography on silica gel (CHCl₃/MeOH/NH₄OH 20:2:1) afforded 1.35 gof a mixture of 5-(N-acetylamino)-5,6,7,8-tetrahydroquinoline and7-(N-acetylamino)-5,6,7,8-tetrahydroquinoline, respectively (49% yield).The mixture (1.35 g, 7.1 mmol) was dissolved in MeOH (20 mL) andconcentrated HCl (5 mL) was added; the solution was then heated atreflux for 2 days. The reaction was then cooled to room temperature andthe volume was reduced by evaporation. The residue was (cautiously) madebasic with a minimum amount of saturated aqueous NaOH, then the aqueousphase was extracted with CHCl₃ (3×25 mL), and the combined organicextracts were dried (MgSO₄) and concentrated in vacuo. Purification ofthe residue by radial chromatography on silica gel (4 mm plate,CHCl₃/MeOH/NH₄OH 20:2:1) afforded two products:7-amino-5,6,7,8-tetrahydroquinoline (AMD8850) (456 mg, 43%) as a paleyellow oil. ¹H NMR (CDCl₃) δ 1.45 (br 2, 2H), 1.48-1.54 (m, 1H),1.88-1.90 (m, 1H), 2.59 (dd, 1H, J=15, 9 Hz), 2.71-2.78 (m, 2H), 3.08(dd, 1H, J=15, 6 Hz), 3.18-3.24 (m, 1H), 6.93 (dd, 1H, J=8, 5 Hz), 7.27(br d, 1H, J=8 Hz), 8.25 (br d, 1H, J=5 Hz); ¹³C NMR (CDCl₃) δ 26.4,31.8, 42.1, 46.8, 120.8, 130.8, 136.1, 146.8, 155.4; ES-MS m/z 149(M+H); and 5-amino-5,6,7,8-tetrahydroquinoline (AMD8851) (503 mg 48%) asa pale yellow oil. ¹H NMR (CDCl₃) δ 1.57-1.65 (m, 3H), 1.78-1.81 (m,1H), 1.93-2.00 (m, 2H), 2.79-2.89 (m, 2H), 3.90-3.92 (m, 1H), 7.04 (dd,1H, J=8, 5 Hz), 7.67 (br d, 1H, J=8 Hz), 8.32 (br d, 1H, J=5 Hz); ¹³CNMR (CDCl₃) δ 19.2, 29.5, 32.3, 33.4, 49.1, 121.2, 135.7, 136.0, 147.5,156.7. ES-MS m/z 149 (M+H).

Example 13 AMD8869: Preparation ofN-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-5-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0195]N-(tert-Butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-5-guinolinyl)-1,4-benzenedimethanamine.

[0196] Using General Procedure B: Reaction of5-amino-5,6,7,8-tetrahydroquinoline (100 mg, 0.67 mmol),N-[1-methylene-4-(carboxaldehyde)phenylene]-N-(tert-butoxycarbonyl)-2-(aminomethyl)pyridine(220 mg, 0.67 mmol) and NaBH(OAc)₃ (286 mg, 1.3 mmol) in CH₂Cl₂ (3 mL)for 18 hours gave, after standard work-up and purification of the crudeintermediate by radial chromatography on silica gel (2 mm plate,CHCl₃/MeOH/NH₄OH 20:2:1), the desired reductive amination product (274mg, 89%) as a colourless oil.

[0197] Using General Procedure D: the oil from above (65 mg, 0.14 mmol)was converted to the corresponding hydrobromide salt with simultaneousdeprotection of the BOC group to give AMD8869 (38 mg, 36%) as a whitesolid. ¹H NMR (D₂O) δ 2.13-2.15 (m, 2H), 2.22-2.27 (m, 1H), 2.29-2.32(m, 1H), 3.17-3.35 (m, 2H), 4.38-4.56 (m, 4H), 4.62 (s, 2H), 4.93 (br s,1H), 7.59 (br s, 5H), 7.85-7.94 (m, 3H), 8.35 (t, 1H, J=7 Hz), 8.60 (d,1H, J=8 Hz), 8.72-8.74 (m, 1H); ¹³C NMR (D₂O) δ 18.6, 26.2, 29.4, 51.3,51.7, 53.9, 56.8, 127.9, 129.6, 129.7, 133.4, 133.9, 134.6, 134.8,145.0, 147.1, 148.7, 149.7, 150.5, 157.6. ES-MS m/z 359 (M+H). Anal.Calcd. for C₂₃H₂₆N₄.4.4HBr.1.4H₂O: C, 37.35; H, 4.52; N, 7.57; Br,47.53. Found: C, 37.43; H, 4.53; N, 7.31; Br, 47.40.

Example 14 AMD8876: Preparation ofN-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-5-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0198] Using General Procedure B:

[0199] Reaction ofN-(tert-Butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-5-quinolinyl)-1,4-benzenedimethanamine(275 mg, 0.60 mmol), imidazole-2-carboxaldehyde (115 mg, 1.2 mmol) andNaBH(OAc)₃ (380 mg, 1.8 mmol) in a mixture of CH₂Cl₂ (5 mL) and aceticacid (0.5 mL) for 48 hours, followed by standard work-up andpurification of the crude intermediate by radial chromatography onsilica gel (2 mm plate, CHCl₃/MeOH/NH₄OH 20:2:1) afforded the desiredreductive amination product (182 mg, 57%) as a pale yellow oil.

[0200] Using General procedure D: the oil from above (182 mg, 0.34 mmol)was converted to the corresponding hydrobromide salt with simultaneousdeprotection of the BOC group to give AMD8876 (157 mg, 49%) as a whitesolid. ¹H NMR (D₂O) δ 1.93-2.10 (m, 2H), 2.23-2.36 (m, 2H), 3.10-3.17(m, 2H), 3.77-3.87 (m, 2H), 4.10 (d, 1H, J=16 Hz), 4.27 (d, 1H, J=16Hz), 4.41 (br s, 3H), 4.69 (br s, 2H), 7.15 (s, 2H), 7.42 (br s, 4H),7.95 (t, 1H, J=6 Hz), 8.03-8.11 (m, 2H), 8.53-8.57 (m, 2H), 8.78-8.81(d, 1H, J=4 Hz), 9.13 (d, 1H, J=6 Hz); ¹³C NMR (D₂O) δ 22.2, 23.1, 30.3,49.8, 50.6, 54.1, 58.2, 63.0, 121.7, 127.5, 130.0, 130.3, 132.0, 132.7,133.2, 141.6, 142.2, 142.6, 147.8, 148.1, 148.3, 148.8, 149.0, 157.0.ES-MS m/z 439 (M+H). Anal. Calcd. for C₂₇H₃₀N₆.5.6HBr.2.3H₂O: C, 34.75;H, 4.34; N, 9.01; Br, 47.95. Found: C, 35.09; H, 4.40; N, 8.62; Br,47.72.

Example 15 AMD8751: Preparation ofN-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0201] To a stirred solution ofN-(tert-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(174 mg, 0.38 mmol) in dry MeOH (5 mL) was added2-imidazolecarboxaldehyde (75 mg, 0.78 mmol) and sodium cyanoborohydride(55 mg, 0.88 mmol) and the mixture was stirred for 40 h. The reactionmixture was concentrated in vacuo and partitioned between CH₂Cl₂ (30 mL)and aqueous 1 N sodium hydroxide (30 mL). The aqueous layer was washedwith CH₂Cl₂ (2×20 mL) and the combined organic extracts washed withbrine (30 mL), dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude product by column chromatography on silica gel(CH₂Cl₂/MeOH, 95:5) afforded the imidazole derivative (48 mg, 24%) as aclear oil.

[0202] To a solution of the intermediate from above (48 mg, 0.089 mmol)in CH₂Cl₂ (2 mL) was added trifluoroacetic acid (1 mL) and the mixturewas stirred at room temperature for 1.5 h. The reaction mixture wasconcentrated in vacuo and the crude oil was purified by columnchromatography on silica gel (CH₂Cl₂/MeOH, 85:15) to afford the freeamine (38 mg, 97%) as a clear oil. Conversion to the hydrobromide saltusing general procedure D gave AMD8751 (37 mg, 45%) as an off-whitesolid. ¹H NMR (D₂O) δ 1.83-1.88 (br m, 1H), 2.22-2.29 (br m, 2H),2.35-2.39 (br m, 1H), 3.01-3.02 (br s, 2H), 3.84 (s, 2H), 4.29 (d, 1H,J=15.9 Hz), 4.31 (s, 2H), 4.42 (d, 1H, J=15.9 Hz), 4.50 (s, 2H),4.60-4.63 (m, 1H), 7.21 (s, 2H), 7.31 (d, 2H, J=7.8 Hz), 7.35 (d, 2H,J=7.8 Hz), 7.76-7.78 (m, 2H), 7.86 (t, 1H, J=6.3 Hz), 8.20-8.24 (br m,1H), 8.34 (d, 1H, J=7.8 Hz), 8.65 (d, 1H, J=5.4 Hz), 8.71 (d, 1H, J=4.4Hz); ¹³C NMR (D₂O) δ 20.47 (2 carbons), 27.79, 49.02, 49.30, 51.12,55.89, 61.55, 119.31 (2 carbons), 125.93, 126.29, 126.41, 130.10, 130.71(4 carbons), 138.56, 139.51, 140.71, 142.77, 145.22, 147.34, 148.06,148.23, 151.09. ES-MS m/z 439 (M+H). Anal. Calcd. forC₂₇H₃₀N₆.4.5HBr.4.0H₂O.1:3CH₃CO₂H: C, 37.31; H, 5.05; N, 8.82; Br,37.74. Found: C, 37.31; H, 4.75; N, 8.90; Br, 37.80.

Example 16 AMD8777: Preparation ofN-(2-pyridinylmethyl)-N′-[(2-amino-3-phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0203] Prepared according to the procedure of Smith, G. A. et al. Org.Synth. 1984, 63, 136-139.

[0204] To a solution of L-Phenylalaninol (358 mg, 2.37 mmol) in wet THF(5 mL) was added di-t-butyl dicarbonate (715 mg, 3.28 mmol). The mixturewas stirred for 16 hours then concentrated in vacuo. Purification of thecrude product by column chromatography on silica gel (hexanes/EtOAc,3:1) afforded the N-Boc-protected alcohol (590 mg, 99%) as a whitesolid: ¹H NMR (CDCl₃) δ 1.41 (br s, 9H), 2.45 (br s, 1H), 2.84 (d, 2H,J=6.0 Hz), 3.52-3.58 (m, 1H), 3.65-3.70 (m, 1H), 3.85-3.88 (br m, 1H),4.76 (br s, 1H), 7.20-7.34 (m, 5H).

[0205] General Procedure F: Oxidation Using Dess-Martin Periodinane:

[0206] To a stirred solution of N-Boc-L-phenylalaninol (258 mg, 1.03mmol) in CH₂Cl₂ (5 mL) was added1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane) (525 mg, 1.24 mmol) in one portion and the mixture wasstirred for 20 min. The reaction mixture was diluted with diethyl ether(30 mL), saturated aqueous sodium bicarbonate (10 mL) and saturatedaqueous sodium thiosulfate (10 mL) and stirred for 30 min. The mixturewas then diluted with water (10 mL) and ethyl acetate (10 mL) and thelayers partitioned. The organic phase was washed with brine (25 mL),dried (MgSO₄) and concentrated in vacuo N-Boc-L-phenylalaninal. This wasused without further purification in the next step.

[0207] Using General procedure A: Reaction ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(250 mg, 0.46 mmol), crude N-Boc L-phenylalaninal and sodiumcyanoborohydride overnight gave the corresponding reductive aminationproduct as a yellow oil (mixture of diastereomers). Using generalprocedures C and D: The intermediate was reacted with thiophenol to givethe free base (60 mg, 22% over 2 steps) as a yellow oil. Conversion tothe corresponding hydrobromide salt with simultaneous deprotection ofthe BOC group gave AMD8777 (73 mg, 91%) as a pale yellow solid (mixtureof diastereomers). ¹H NMR (D₂O) two diastereomers δ 1.61-1.73 (br m,1H), 1.94-2.22 (m, 3H), 2.65-2.81 (m) and 2.88-2.92 (m) and 2.97-3.16(m) and 3.64 (br s) and 3.74-3.80 (m) (total 9H), 4.31-4.37 (m) and 4.32(s) and 4.36 (s) (total 3H), 4.49 (s) and 4.54 (s) (total 2H), 7.14 (d,J=8.5 Hz) and 7.26-7.42 (m) (total 9H), 7.67-7.71 (m) and 7.75-7.81 (m)and 8.20 (d, J=9.7 Hz) and 8.25 (d, J=8.5 Hz) and 8.36 (d, J=6.0 Hz) and8.54 (d, J=6.0 Hz) and 8.69 (br s) (total 7H); ¹³C NMR (D₂O) twodiastereomers δ 19.33, 20.18, 20.48, 20.54, 27.89, 36.86, 37.04, 49.00,51.08, 51.24, 51.34, 52.17, 53.00, 54.83, 55.02, 57.58, 58.27, 62.69,125.60, 125.73, 126.67, 126.73, 128.03, 128.10, 129.54, 129.62, 129.75,130.12, 130.27, 130.94, 135.73, 139.22, 139.32, 139.38, 139.63, 140.40,140.91, 143.48, 143.66, 146.69, 146.81, 147.75, 151.14, 151.73. ES-MSm/z 492 (M+H). Anal. Calcd. for C₃₂H₃₇N₅.4.0HBr.3.7H₂O: C, 43.58; H,5.53; N, 7.94; Br, 36.24. Found: C, 43.65; H, 5.23; N, 7.86; Br, 36.03.

Example 17 AMD8763: Preparation ofN-(2-pyridinylmethyl)-N′-(1H-imidazol-4-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0208] Using general procedure A: Reaction ofN-(tert-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(215 mg, 0.47 mmol), 4(5)-imidazolecarboxaldehyde (105 mg, 1.09 mmol)and sodium cyanoborohydride overnight gave the corresponding reductiveamination product (145 mg, 59%) as a clear foam.

[0209] Using General Procedures C and D: The intermediate from above(145 mg, 0.28 mmol) gave AMD8763 (170 mg, 68%) as a white solid. ¹H NMR(D₂O) δ 1.72-1.78 (br m, 1H), 2.07-2.18 (br m, 2H), 2.27-2.32 (br m,1H), 2.91 (br d, 2H, J=4.8 Hz), 3.78 (d, 1H, J=13.5 Hz), 3.83 (d, 1H,J=13.8 Hz), 4.00 (d, 1H, J=14.7 Hz), 4.08 (d, 1H, J=14.7 Hz), 4.35 (s,2H), 4.35-4.42 (m, 1H), 4.63 (s, 2H), 7.35 (s, 4H), 7.43 (s, 1H), 7.71(dd, 1H, J=8.1, 7.8 Hz), 7.96 (dd, 1H, J=6.9, 6.6 Hz), 8.02 (d, 1H,J=7.8 Hz), 8.19 (d, 1H, J=8.1 Hz), 8.46-8.51 (m, 2H), 8.60 (s, 1H), 8.78(d, 1H, J=5.3 Hz). ¹³C NMR (D₂O) δ 19.76, 20.49, 27.66, 46.78, 47.80,51.61, 54.57, 59.34, 118.33, 125.48, 127.78, 128.10, 129.55, 130.64 and130.69 (total 5 carbons), 134.27, 139.25, 139.54, 140.15, 144.72,146.01, 146.50, 147.44, 151.97. ES-MS m/z 439 (M+H). Anal. Calcd. forC₂₇H₃₀N₆.4.5HBr.2.4H₂O.0.7CH₃CO₂H: C, 38.42; H, 4.78; N, 9.46; Br,40.49. Found: C, 38.30; H, 4.78; N, 9.40; Br, 40.51.

Example 18 AMD8771: Preparation ofN-(2-pyridinylmethyl)-N′-(2-quinolinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0210] Using general Procedure A: Reaction ofN-(tert-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(130 mg, 0.28 mmol) with 2-quinolinecarboxaldehyde (95 mg, 0.61 mmol)and sodium cyanoborohydride overnight gave the corresponding reductiveamination product (60 mg, 36%) as an orange foam.

[0211] Using general procedure D: the intermediate from above (60 mg,0.28 mmol) was converted to the hydrobromide salt with simultaneousdeprotection of the BOC group to give the crude product. The solid wasthen re-dissolved in dry MeOH (1 mL) and precipitated with diethylether. The solid was washed by decantation with ether (3×20 mL) and theremaining traces of solvent were removed by evaporation under reducedpressure followed by drying in vacuo to afford AMD8771 (71 mg, 79%) asan orange solid. ¹H NMR (D₂O) δ 1.84-1.92 (br m, 1H), 2.19-2.34 (m, 2H),2.47-2.51 (br m, 1H), 3.02 (br s, 2H), 3.73 (s, 2H), 3.81 (d, 1H, J=13.2Hz), 3.88 (d, 1H, J=12.9 Hz), 4.18 (s, 2H), 4.54 (d, 1H, J=16.8 Hz),4.72 (d, 1H, J=16.8 Hz), 4.75-4.79 (m, overlap with HOD, 1H), 6.97 (d,2H, J=8.0 Hz), 7.20 (d, 2H, J=8.0 Hz), 7.64 (d, 1H, J=8.0 Hz), 7.69-7.79(m, 2H), 7.87-7.95 (m, 2H), 8.03-8.11 (m, 3H), 8.18 (t, 1H, J=8.0 Hz),8.37 (d, 1H, J=8.0 Hz), 8.66 (d, 1H, J=5.0 Hz), 8.75 (d, 1H, J=6.0 Hz),8.83 (d, 1H, J=8.3 Hz); ¹³C NMR (D₂O) δ 20.47, 20.79, 27.96, 48.87,50.32, 56.69, 56.83, 62.87, 119.83, 122.45, 126.06, 126.36, 126.49,128.07, 129.52, 129.83, 130.17, 130.47 (2 carbons), 130.95 (2 carbons),135.45, 137.25, 139.02, 139.77, 141.17, 142.98, 147.08, 147.45, 147.89,148.18, 150.83, 157.51. ES-MS m/z 500 (M+H). Anal. Calcd. forC₃₃H₃₃N₅.4.0HBr.3.1H₂O: C, 45.10; H, 4.89; N, 7.93; Br, 36.25. Found: C,45.08; H, 4.95; N, 7.97; Br, 36.36.

Example 19 AMD8778: Preparation ofN-(2-pyridinylmethyl)-N′-(2-(2-naphthoyl)aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0212] N-2-(2-naphthoyl)ethanolamine

[0213] To a stirred solution of 2-naphthoic acid (665 mg, 3.87 mmol) andethanolamine (0.24 mL, 3.87 mmol) in dry CH₂Cl₂ (10 mL) was addedN,N-diisopropylethylamine (2 mL, 11.5 mmol), 1-hydroxybenzotriazolehydrate (680 mg, 5.04 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDC) (1.00 g, 5.22 mmol) and the mixture was stirredat room temperature for 18 h. The reaction mixture was diluted withCH₂Cl₂ (25 mL) and brine (30 mL) and the aqueous layer was separated andextracted with CH₂Cl₂ (2×25 mL). The combined organic phases were dried(MgSO₄), filtered and evaporated in vacuo to give the crude product as awhite solid. Purification of the solid by column chromatography onsilica gel (EtOAc) gave the title compound (660 mg, 79%) as a whitesolid. ¹H NMR (CDCl₃) δ 2.71 (br s, 1H), 3.70 (q, 2H, J=6.0 Hz), 3.89(q, 2H, J=6.0 Hz), 6.82 (br s, 1H), 7.51-7.58 (m, 2H), 7.84-7.90 (m,4H), 8.31 (s, 1H).

[0214] Using General Procedure F: The alcohol from above (200 mg, 0.93mmol) was then oxidized to the corresponding aldehyde using theDess-Martin procedure with Dess-Martin periodinane (535 mg, 1.26 mmol)and used without further purification in the next step.

[0215] Using general Procedure A: Reaction of the aldehyde from abovewithN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(224 mg, 0.41 mmol) and sodium cyanoborohydride gave, followingpurification, the corresponding reductive amination product as an orangeoil.

[0216] Using General Procedures C and D: Reaction of the oil withthiophenol gave the free base (63 mg, 28% over 2 steps) as a pale orangeoil which was subsequently converted to the hydrobromide salt givingAMD8778 (93 mg, 89%) as a pale yellow solid. ¹H NMR (CD₃OD) δ 1.79-1.84(br m, 1H), 2.11-2.22 (br m, 2H), 2.53-2.58 (br m, 1H), 2.88-2.97 (br m,2H), 3.17 (t, 1H, J=10.8 Hz), 3.35-3.58 (m, 3H), 4.22-4.40 (br m, 4H),4.50-4.66 (m, 1H), 4.65 (s, 2H), 7.32 (br m, 1H), 7.59-7.70 (m, 4H),7.75-7.82 (m, 5H), 7.91 (d, 1H, J=8.0 Hz), 7.98-8.09 (m, 4H), 8.30 (td,1H, J=8.0, 1.0 Hz), 8.48 (br s, 1H), 8.78 (d, 1H, J=5.6 Hz); ¹³C NMR(CD₃OD) δ 14.44, 20.58, 27.42, 36.73, 50.82, 53.65, 54.60, 61.14, 65.92,124.00, 124.55, 125.60, 125.74, 127.22, 127.94, 128.38, 128.38, 128.53,128.62, 129.19, 130.51, 131.21 (2 carbons), 131.37 (2 carbons), 132.38,132.96, 135.56, 136.48, 141.89, 141.95, 145.30, 146.96, 148.98, 149.84,171.26. ES-MS m/z 556 (M+H). Anal. Calcd. for C₃₆H₃₇N₅O.3.6HBr.3.8H₂O:C, 47.23; H, 5.31; N, 7.65; Br, 31.42. Found: C, 47.18; H, 5.10; N,7.53; Br, 31.47.

Example 20 AMD8781: Preparation ofN-(2-pyridinylmethyl)-N′-[(S)-(2-acetylamino-3-phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt of the low polarity diastereomer)

[0217] N-Acetyl-L-Phenylalaninal:

[0218] To a stirred solution of L-phenylalaninol (228 mg, 1.51 mmol) inTHF (5 mL) was added acetic anhydride (0.15 mL, 1.59 mmol) and themixture stirred for 16 h. The reaction mixture was diluted with EtOAc(10 mL) and washed with 1 N HCL (15 mL), saturated aqueous sodiumbicarbonate (15 mL) and brine (15 mL). The organic phase was dried(MgSO₄), filtered and concentrated in vacuo. Purification of the residueby column chromatography on silica gel afforded the N-acetylated alcohol(220 mg, 75%) as a white solid. ¹H NMR (CDCl₃) δ 1.95 (s, 3H), 2.87 (d,2H, J=6.0 Hz), 3.17 (br s, 1H), 3.56-3.68 (m, 2H), 4.13-4.21 (m, 1H),5.97 (br d, 1H, J=6.0 Hz), 7.20-7.34 (m, 5H). The alcohol was thenoxidized according to the general Dess-Martin procedure and the crudealdehyde used without further purification.

[0219] Reaction ofN-(tert-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(268 mg, 0.58 mmol) and crude N-acetyl-L-phenylalaninal gave the desiredproduct (196 mg, 53%) as a mixture of diastereomers. The diastereomerswere separated and purified by column chromatography with silica gel(CH₂Cl₂/MeOH, 96:4) followed by preparative thin layer chromatography(CH₂Cl₂/MeOH, 95:5) a low polarity diastereomer (73 mg) and a highpolarity diastereomer (50 mg), each as a clear oil.

[0220] Using general procedure D: The low polarity diastereomer (73 mg,0.12 mmol) was converted to the hydrobromide salt with simultaneousdeprotection of the BOC group to afford AMD8781 (84 mg, 85%) as a paleyellow solid. ¹H NMR (D₂O): low polarity diastereomer: δ 1.64-1.69 (brm, 1H), 1.83 (br s, 3H), 1.94-2.24 (m, 3H), 2.67-2.74 (m, 1H), 2.79-2.84(br m, 3H), 2.92-3.00 (m, 1H), 3.40 (d, 1H, J=13.8 Hz), 4.02-4.13 (br m,1H), 4.38-4.42 (br s, 5H), 4.56 (s, 2H), 7.23-7.37 (m, 5H), 7.45-7.55(br m, 5H), 7.76-7.82 (m, 1H), 7.84 (d, 2H, J=8.0 Hz), 8.28 (t, 1H,J=8.0), 8.49 (br d, 1H, J=2.0 Hz), 8.70 (d, 1H, J=4.0 Hz); ¹³C NMR (D₂O)δ 20.32, 20.46, 22.21, 27.44, 37.47, 48.46, 49.26, 51.40, 54.74, 55.60,61.44, 125.11, 127.23, 127.37, 127.56, 129.33 (2 carbons), 129.55 (2carbons), 131.22 (2 carbons), 131.44 (2 carbons), 131.57, 134.44,137.26, 137.40, 141.80, 144.74, 145.01, 145.75, 146.88, 149.53, 175.66.ES-MS m/z 534 (M+H). Anal. Calcd. for C₃₄H₃₉N₅O.3.8HBr.2.9H₂O: C, 45.71;H, 5.48; N, 7.84; Br, 33.99. Found: C, 45.74; H, 5.52; N, 7.71; Br,34.06.

Example 21 AMD8782: Preparation ofN-(2-pyridinylmethyl)-N′-[(S)-(2-acetylamino-3-phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt of the high polarity diastereomer)

[0221] Using general procedure D: The high polarity diastereomer fromabove (50 mg, 0.08 mmol) was converted to the hydrobromide salt withsimultaneous deprotection of the BOC group to afford AMD8782 (37 mg,55%) as a white solid. ¹H NMR (D₂O): high polarity diastereomer: δ1.65-1.69 (br m, 1H), 1.85-1.93 (m, 1H), 1.87 (s, 3H), 2.02-2.08 (br m,1H), 2.26-2.29 (br m, 1H), 2.56-2.71 (m, 2H), 2.72-2.82 (br m, 2H),3.17-3.22 (br m, 2H), 3.77-3.83 (m, 1H), 4.10 (s, 2H), 4.36-4.44 (m,1H), 4.43 (s, 2H), 4.55 (d, 1H, J=16.2 Hz), 4.64 (d, 1H, J=16.2 Hz),7.01 (d, 2H, J=7.0 Hz), 7.16-7.27 (m, 3H), 7.49 (s, 4H), 7.49-7.52 (m,1H), 7.86 (d, 1H, J=8.0 Hz), 7.93-8.01 (m, 2H), 8.44-8.49 (m, 2H), 8.76(d, 1H, J=5.0 Hz); ¹³C NMR (D₂O) δ 20.41, 20.67, 22.28, 27.38, 38.53,47.93, 51.20, 51.52, 56.42, 56.51, 56.79, 125.31, 127.37, 127.60,127.84, 129.17 (2 carbons), 129.47 (2 carbons), 131.10 and 131.22 (total5 carbons), 137.41, 137.35, 137.49, 143.07, 143.54, 145.11, 145.97,146.31, 149.93, 175.01. ES-MS m/z 534 (M+H). Anal. Calcd. forC₃₄H₃₉N₅O.3.8HBr.2.7H₂O: C, 45.89; H, 5.46; N, 7.87; Br, 34.12. Found:C, 45.95; H, 5.56; N, 7.70; Br, 34.01.

Example 22 AMD8788: Preparation ofN-(2-pyridinylmethyl)-N′-[3-((2-naphthalenylmethyl)amino)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0222] To a solution of 3-amino-1-propanol (0.43 mL, 5.56 mmol) and2-naphthaldehyde (787 mg, 5.05 mmol) in MeOH (10 mL) was added sodiumcyanoborohydride (460 mg, 7.3 mmol) and the mixture stirred for 17 h.The resultant crude yellow oil was then stirred with di-t-butyldicarbonate (1.20 g, 5.60 mmol) in wet THF (40 mL) for 1 hour. Afterwork-up, the residue was purified by column chromatography on silica gel(hexanes/EtOAc, 3:1) to give3-[N-t-butyloxycarbonyl[N-(2-naphthalenylmethyl)]amino]propanol (1.50 g,60% over 2 steps) as a clear oil: ¹H NMR (CDCl₃) δ 1.49 (br s, 9H), 1.65(br s, 1H), 3.46-3.49 (br m, 2H), 3.58-3.63 (br m, 2H), 3.75-3.78 (m,1H), 4.55 (s, 2H), 7.37 (br d, 1H, J=8.4 Hz), 7.47-7.50 (m, 2H), 7.64(s, 1H), 7.79-7.84 (m, 3H).

[0223] Using general procedure F: The alcohol (230 mg, 0.73 mmol) wasoxidized in CH₂Cl₂ (5 mL) with Dess Martin periodinane (370 mg, 0.87mmol) for 20 min to give the crude aldehyde which was used withoutfurther purification in the next step.

[0224] To a solution ofN-(tert-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(260 mg, 0.57 mmol) and the crude naphthyl aldehyde from above in MeOH(15 mL) was added sodium cyanoborohydride (62 mg, 0.98 mmol) and themixture stirred for 16 h. After work-up, the crude material was purifiedby column chromatography on silica gel (CH₂Cl₂/MeOH, 96:4) give thedesired intermediate (230 mg, 53%) as a colorless oil.

[0225] Using general procedure D: the oil from above (125 mg, 0.17 mmol)was converted to the hydrobromide salt with simultaneous deprotection ofthe BOC group and the solid that formed was re-precipitated frommethanol/ether to give AMD8788 (126 mg, 83%) as a beige solid. ¹H NMR(D₂O) δ 1.58-1.63 (br m, 1H), 1.81-2.04 (br m, 4H), 2.13-2.22 (br m,1H), 2.71-2.75 (br m, 2H), 2.84-3.11 (br m, 4H), 3.89 (d, 1H, J=13.2Hz), 3.99 (d, 1H, J=13.2 Hz), 4.22-4.27 (m, 1H), 4.31 (s, 2H), 4.36 (s,2H), 4.61 (s, 2H), 7.36-7.51 (m, 8H), 7.75-8.02 (m, 7H), 8.31 (d, 1H,J=5.0 Hz), 8.45 (dd, 1H, J=12.0, 7.0 Hz), 8.75 (d, 1H, J=6.0 Hz); ¹³CNMR (D₂O) δ 20.32 (2 carbons), 23.31, 27.35, 44.34, 47.69, 48.78, 51.15,51.58, 55.10, 60.32, 125.04, 126.91, 127.55, 127.86 (2 carbons), 128.21(2 carbons), 128.40, 129.56, 130.19, 130.87, 131.05 (2 carbons), 131.33(2 carbons), 133.10, 133.46, 135.48, 137.50, 143.06, 143.32, 144.55,145.79, 146.72, 146.90, 150.08. ES-MS m/z 556 (M+H). Anal. Calcd. forC₃₇H₄₁N₅.4.8HBr.2.2H₂O: C, 45.17; H, 5.14; N, 7.12; Br, 38.99. Found: C,45.16; H, 5.25; N, 6.87; Br, 39.16.

Example 23 AMD8733 and AMD8734: Preparation ofN-(2-pyridinylmethyl)-N′-[2-(S)-pyrollidinylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0226] To a solution of N-Boc-L-prolinol ((S)-N-BOC-pyrrolidinemethanol)(402 mg, 2.0 mmol) in dichloromethane (20 mL) was added TPAP (70 mg, 0.2mmol), NMO (351 mg, 3.0 mmol) and 4 A molecular sieves (1 g). Themixture was then stirred at room temperature for one hour. Followingfiltration of the material through celite, the mixture was concentratedand the residue was purified by column chromatography on silica gel (10%methanol in dichloromethane) to afford the corresponding aldehyde (320mg, 80%).

[0227] The N-BOC-prolinal (320 mg, 1.6 mmol) from above was thendissolved in methanol (12 mL) to which,N-(tert-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(360 mg, 0.80 mmol) was added. The reaction mixture was stirred at roomtemperature for one hour, then sodium cyanoborohydride (113 mg, 1.80mmol) was added (see general procedure A). Following work-up, the crudeintermediate was purified by column chromatography on silica gel (5%methanol in dichloromethane) to give two diastereomeric products, inyields of 80 mg (16%) and 64 mg (13%) respectively.

[0228] Using general procedure D: the two diastereomeric products wereconverted to their corresponding hydrobromide salts with simultaneousdeprotection of the BOC groups to give 62 mg of AMD8733 and 41 mg ofAMD8734, respectively.

[0229] AMD8733: ¹H NMR (D₂O) δ 1.61-1.67 (m, 2H), 1.94-2.29 (m, 6H),2,85 (br s, 2H), 3.06 (d, 2H, J=6.6 Hz), 3.32 (t, 2H, J=7.2 Hz), 3.80(br s, 2H), 3.80 (m, 1H), 4.26 (s, 2H), 4.33 (dd, 1H, J=9.0, 3.6 Hz),4.43 (s, 2H), 7.33 (m, 4H), 7.67 (m, 3H), 8.13 (m, 2H), 8.34 (d, 1H,J=4.8 Hz), 8.78 (d, 1H, J=4.3 Hz); ¹³C NMR (D₂O) δ 19.83, 20.79, 23.31,27.78, 28.52, 45.65, 49.43, 51.05, 53.94, 56.01, 58.99, 61.20, 125.37,126.00, 126.17, 130.11, 130.70, 130.79, 136.36, 139.07, 138.33, 140.14,142.27, 147.41, 147.52, 151.62. ES-MS m/z 442 (M+H). Anal. Calcd. forC₂₈H₃₅N₅.4.6HBr.4.8 H₂O.1.0AcOH: C, 37.52; H, 5.58; N, 7.29; Br, 38.27.Found: C, 37.19; H, 5.26; N, 7.30; Br, 38.39.

[0230] AMD8734: ¹H NMR (D₂O) δ 1.61 (dd, 1H, J=12.9, 8.4 Hz), 1.67 (m,1H), 1.94 (qi, 2H, J=7.4 Hz), 2.03 (m, 2H), 2.09 (m, 2H), 2.29 (m, 1H),2.75 (dd, 1H, J=14.7, 10.2 Hz), 2.92 (m, 1H), 3.07 (m, 1H), 3.18 (m,1H), 3.23 (dd, 1H, 7.5, 3.9 Hz), 3.69 (m, 2H), 3.83 (m, 1H), 4.33 (s,2H), 4.41 (m, 1H), 4.57 (s, 2H), 7.41 (br s, 4H), 7.79 (m, 3H), 8.25 (m,2H), 8.50 (d, 1H, 4.1 Hz), 8.77 (d, 1H, J=5.3 Hz); ¹³C NMR (D₂O) δ14.50, 19.36, 20.48, 20.79, 22.32, 27.67, 27.84, 45.12, 48.80, 51.34,51.85, 54.94, 58.16, 58.90, 125.62, 126.86, 130.22, 130.90, 139.34,139.54, 140.69, 144.02, 146.41, 147.48, 147.67, 151.87. ES-MS m/z 442(M+H). Anal. Calcd. for C₂₈H₃₅N₅.4.8HBr.3.6 H₂O.1.0AcOH: C, 37.73; H,5.38; N, 7.33. Found: C, 37.89; H, 5.41; N, 7.36.

Example 24 AMD8756: Preparation ofN-(2-pyridinylmethyl)-N′-[2-(R)-pyrollidinylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0231] In a similar manner to the procedure described above,(R)-pyrrolidinemethanol gave two diastereomeric products, 111 mg and 58mg, respectively. The less-polar diastereomer (111 mg) was thenconverted to the corresponding hydrobromide salt with simultaneousdeprotection of the BOC group to give AMD8756 (81 mg). ¹H NMR (D₂O) δ1.61-1.67 (m, 2H), 1.94-2.29 (m, 6H), 2,85 (br s, 2H), 3.06 (d, 2H,J=6.6 Hz), 3.32 (t, 2H, J=7.2 Hz), 3.80 (br s, 2H), 3.80 (m, 1H), 4.26(s, 2H), 4.33 (dd, 1H, J=9.0, 3.6 Hz), 4.43 (s, 2H), 7.33 (m, 4H), 7.67(m, 3H), 8.13 (m, 2H), 8.34 (d, 1H, J=4.8 Hz), 8.78 (d, 1H, J=4.3 Hz);¹³C NMR (D₂O) δ 19.94, 20.63, 23.30, 27.86, 28.62, 45.80, 48.62, 51.42,54.04, 56.05, 59.12, 61.08, 125.47, 127.15, 127.24, 129.96, 130.83,130.93, 139.19, 139.49, 140.20, 144.72, 146.06, 147.13, 147.51, 151.62.ES-MS m/z 442 (M+H). Anal. Calcd. for C₂₈H₃₅N₅.3.9HBr.4.2H₂O: C, 40.38;H, 5.72; N, 8.41; Br, 37.42. Found: C, 40.38; H, 5.53; N, 8.17; Br,37.55.

Example 25 AMD8799: Preparation ofN-(2-pyridinylmethyl)-N′-[3-pyrazolylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0232] Using general procedure A: Reaction of 3-pyrazolecarboxaldehyde(85 mg, 0.88 mmol) andN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(320 mg, 0.589 mmol) with sodium cyanoborohydride (55 mg, 0.883 mmol)followed by purification of the crude material by column chromatographyon silica gel (5% methanol in dichloromethane), gave the desired product(166 mg, 45%).

[0233] Using general procedures C and D: the intermediate from above wasreacted with thiophenol (0.17 mL, 1.67 mmol) and potassium carbonate(290 mg, 2.09 mmol) in acetonitrile (10 mL). After work-up, the crudematerial was purified by column chromatography on silica gel (10%methanol in dichloromethane) to give the free base of the desiredproduct (108 mg, 59%). Conversion to the hydrobromide salt gave AMD8799(88 mg). ¹H NMR (D₂O) δ 1.72 (m, 1H), 2.11 (m, 2H), 2.31 (m, 1H), 2.62(s, 1H), 2.86 (s, 2H), 3.30, 3.63 (s, total of 1H), 4.00 (s, 2H), 4.10(d, 1H, J=15.3 Hz), 4.20 (d, 1H, J=15.3 Hz), 4.29 (s, 2H), 4.34 (m, 1H),4.55 (s, 2H), 6.56 (br s, 1H), 7.26 (s, 4H), 7.59 (d, 1H, J=8.1 Hz),7.80 (m, 3H), 7.95 (d, 1H, J=8.1 Hz), 8.11 (dd, 1H, J=8.4, 5.3 Hz), 8.56(d, 1H, J=5.8 Hz), 8.81 (d, 1H, J=5.3 Hz); ¹³C NMR (D₂O) δ 20.10, 27.59,48.05, 48.65, 51.47, 55.34, 60.11, 107.27, 125.36, 126.97, 130.97,133.61, 138.99, 141.33, 144.51, 146.20, 147.32, 150.96. ES-MS m/z 439(M+H). Anal. Calcd. for C₂₇H₃₀N₆.5.3HBr.1.3H₂O.1.4HOAc: C, 36.46; H,4.69; N, 8.98; Br, 45.26. Found: C, 36.57; H, 5.00; N, 9.13; Br, 45.11.

Example 26 AMD8728: Preparation ofN-(2-pyridinylmethyl)-N′-[2-pyrrolylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine

[0234] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.229 g, 0.420 mmol) in anhydrous methanol (4.2 mL, concentration ˜0.1M), at room temperature, was added pyrrole-2-carboxaldehyde (0.0960 g,1.00 mmol, ˜2 equiv.) as a solid in one portion. Once the aldehyde haddissolved (˜5 minutes), NaBH₃CN (0.106 g, 1.68 mmol, ˜4 equiv.) wasadded in one portion and the resultant solution was stirred at roomtemperature for 115 hours. The solvent was removed under reducedpressure and CH₂Cl₂ (40 mL) and 1.0M NaOH (10 mL) were added to theresidue. The phases were separated and the aqueous phase was extractedwith CH₂Cl₂ (3×10 mL). The combined organic phases were dried (Na₂SO₄)and concentrated. Purification of the crude material by radialchromatography on silica gel (2 mm plate, eluant 25:1 CH₂Cl₂-MeOH)provided the desired intermediate (0.178 g, 68%) as a white solid.

[0235] To a stirred solution of the solid from above (0.178 g, 0.286mmol) in anhydrous CH₃CN (5.5 mL, concentration ˜0.05 M), at roomtemperature, was added thiophenol (0.15 mL, 1.461 mmol, ˜5 equiv.)followed by powdered K₂CO₃ (0.331 g, 2.40 mmol, ˜8 equiv.). Theresultant bright yellow solution was stirred for 1 hour at roomtemperature. The solvent was removed under reduced pressure and CH₂Cl₂(10 mL) and water (1 mL) were added to the residue. The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×5 mL). Thecombined organic phases were dried (Na₂SO₄) and concentrated.Purification of the crude material by column chromatography on silicagel (20:1 CH₂Cl₂-MeOH) afforded AMD8728 (0.085 g, 68%) as a yellow oil.¹H NMR (CDCl₃) δ 1.57-1.70 (m, 1H), 1.84-2.14 (m, 3H), 2.40 (br s, 1H,NH), 2.64-2.72 (m, 1H), 2.80-2.89 (m, 1H), 3.58 (d, 1H, J=14.1 Hz), 3.66(s, 2H), 3.77 (d, 1H, J=14.1 Hz), 3.80 (s, 2H), 3.91 (s, 2H), 4.02 (m,1H), 5.20 (br s, 1H), 6.09 (dd, 1H, J=3.0, 3.0 Hz), 6.79 (dd, 1H, J=3.0,3.0 Hz), 7.07 (dd, 1H, J=12.3, 4.8 Hz), 7.14 (dd, 1H, J=6.0, 4.8 Hz),7.25-7.41 (m, 6H), 7.62 (td, 1H, J=7.8, 1.8 Hz), 8.53 (m, 2H), 10.78 (brs, 1H); ¹³C NMR (CDCl₃) δ 21.21, 24.06, 29.48, 47.33, 53.69, 54.11,54.89, 59.21, 105.98, 107.78, 117.16, 122.14, 122.35, 122.79, 128.55 (2carbons), 129.14 (2 carbons), 131.21, 134.84, 136.86, 137.25, 138.91,139.44, 147.37, 149.68, 158.62, 160.15. ES-MS m/z 438 (M+H). Anal.Calcd. for C₂₈H₃₁N₅.0.8CH₃OH: C, 74.68; H, 7.44; N, 15.12. Found: C,74.93; H, 7.33; N, 15.12.

Example 27 AMD8836: Preparation ofN-(2-pyridinylmethyl)-N′-[2-thiopheneylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0236] To a stirred solution ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.280 g, 0.610 mmol) in anhydrous methanol (6 mL), at room temperature,was added thiophene-2-carboxaldehyde (0.25 mL, 2.67 mmol) followed byNaBH₃CN (0.081 g, 1.30 mmol) and the resultant solution was stirred atroom temperature. After 1 day, an additional amount of NaBH₃CN (0.083 g,1.31 mmol) was added and the solution was stirred at room temperaturefor an additional 3 days. The solvent was removed under reduced pressureand CH₂Cl₂ (30 mL) and water (10 mL) were added to the residue. Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(3×10 mL). The combined organic phases were dried (Na₂SO₄) andconcentrated. Purification of the crude material by radialchromatography on silica gel (2 mm plate, 40:1 CH₂Cl₂-MeOH) provided0.173 g of the desired amine as a yellow oil.

[0237] Using general procedure D: the oil from above was converted tothe hydrobromide salt with simultaneous deprotection of the BOC group toafford AMD8836 (0.225 g) as a white solid. ¹H NMR (D₂O) δ 1.60-1.76 (m,1H), 2.04-2.16 (m, 2H), 2.33-2.38 (m, 1H), 2.82-2.85 (m, 2H), 4.09 (d,1H J=13.5 Hz), 4.16 (d, 1H J=13.5 Hz), 4.29 (d, 1H J=14.4 Hz), 4.39 (d,1H J=14.4 Hz), 4.39 (s, 2H), 4.46 (dd, 1H J=7.8, 5.7 Hz), 4.61 (s, 2H),6.99 (dd, 1H J=3.6, 4.8 Hz), 7.16 (d, 1H J=3.0 Hz), 7.41-7.52 (m, 6H),7.87-7.92 (m, 2H), 7.97 (d, 1H J=8.1 Hz), 8.39-8.44 (m, 2H), 8.75 (d,1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 20.29, 20.43, 27.49, 48.27, 50.14, 51.48,54.64, 59.65, 124.97, 127.31, 127.47, 127.93, 128.24, 130.27, 130.72,130.91 (2 carbons), 131.18 (2 carbons), 136.31, 136.65, 138.00, 142.77,143.56, 145.29, 145.52, 146.75, 150.92; ES-MS m/z 455 (M+H). Anal.Calcd. for C₂₈H₃₀N₄S.4.0HBr.1.9H₂O: C, 41.39; H, 4.69; N, 6.90; Br,39.34; S, 3.95. Found: C, 41.45; H, 4.72; N, 6.90; Br, 39.30; S, 3.87.

Example 28 AMD8841: Preparation ofN-(2-pyridinylmethyl)-N′-[2-thiazolylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0238] To a stirred solution ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.295 g, 0.643 mmol) in anhydrous methanol (6.5 mL), at roomtemperature, was added thiazole-2-carboxaldehyde (0.33 mL, 3.76 mmol)followed by NaBH₃CN (0.131 g, 2.09 mmol) and the resultant solution wasstirred at room temperature. After 2 days, an additional amount ofNaBH₃CN (0.134 g, 2.10 mmol) was added and the solution was stirred atroom temperature for an additional 4 days. The solvent was removed underreduced pressure and CH₂Cl₂ (20 mL) and water (10 mL) were added to theresidue. The phases were separated and the aqueous phase was extractedwith CH₂Cl₂ (3×10 mL). The combined organic phases were dried (Na₂SO₄)and concentrated. Purification of the crude material by radialchromatography on silica gel (2 mm plate, 40:1 CH₂Cl₂-MeOH containing 1%NH₄OH) afforded 0.164 g of the protected amine as a yellow oil.

[0239] Using general procedure D: the oil from above was converted tothe hydrobromide salt with simultaneous deprotection of the BOC group toprovide AMD8841 (0.178 g) as a white solid. ¹H NMR (D₂O) δ 1.71-1.79 (m,1H), 2.08-2.19 (m, 2H), 2.29-2.35 (m, 1H), 2.92-2.95 (m,-2H), 3.91 (s,2H), 4.31 (s, 2H), 4.37 (d, 1H J=16.5 Hz), 4.43-4,58 (m, 4H), 7.37 (d,2H J=8.1 Hz), 7.43 (d, 2H J=8.1 Hz), 7.74-7.89 (m, 5H), 8.22-8.32 (m,2H), 8.56 (d, 1H, J=5.7 Hz), 8.71 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ20.38, 20.52, 27.75, 48.69, 51.32, 51.99, 55.52, 59.93, 123.57, 125.78,126.91, 126.97, 130.16, 130.76 (2 carbons), 130.97 (2 carbons), 136.70,138.74, 139.68, 140.66, 144.22, 146.28, 147.37, 147.73, 151.26, 173.19.ES-MS m/z 456 (M+H). Anal. Calcd. for C₂₇H₂₉N₅S.3.9HBr.1.9H₂O: C, 40.27;H, 4.59; N, 8.70; Br, 38.69; S, 3.98. Found: C, 40.40; H, 4.59; N, 8.43;Br, 38.53; S, 3.92.

Example 29 AMD8821: Preparation ofN-(2-pyridinylmethyl)-N′-[2-furanylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0240] To a stirred solution ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.206 g, 0.449 mmol) in anhydrous methanol (10 mL), at roomtemperature, was added furfural (0.19 mL, 2.29 mmol) followed by NaBH₃CN(0.070 g, 1.11 mmol) and the resultant solution was stirred at roomtemperature overnight. The solvent was removed under reduced pressureand CH₂Cl₂ (20 mL) and 1.0 M aqueous NaOH (10 mL) were added to theresidue. The phases were separated and the aqueous phase was extractedwith CH₂Cl₂ (3×10 mL). The combined organic phases were dried (Na₂SO₄)and concentrated. Purification of the crude material by columnchromatography silica gel (25:1 CH₂Cl₂-MeOH) provided 0.103 g of theprotected amine as a yellow oil.

[0241] Using general procedure D: the oil from above was converted tothe hydrobromide salt with simultaneous deprotection of the BOC group toafford AMD8821 (0.086 g) as a purple solid. ¹H NMR (D₂O) δ 1.67-1.78 (m,1H), 2.06-2.17(m, 2H), 2.28-2.37 (m, 1H), 2.83 (br d, 2H, J=5.7 Hz),4.11-4.24 (m, 4H), 4.38 (s, 2H), 4.44 (dd, 1H, J=10.5, 6.0 Hz), 4.58 (s,2H), 6.30 (br s, 1H), 6.46 (d, 1H, J=3.3 Hz), 7.40-7.55 (m, 6H),7.81-7.91 (m, 3H), 8.34 (br t, 1H, J=8.1 Hz), 8.41 (br d, 1H, J=4.8 Hz),8.72 (br d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 20.27, 20.51, 27.45, 47.90,48.73, 51.35, 55.29, 60.21, 111.34, 112.65, 124.70, 126.85, 126.90,130.87 (3 carbons), 131.16(2 carbons), 136.11, 137.50, 142.80, 143.15,144.10, 144.52, 146.31, 147.44, 147.69, 150.91. ES-MS m/z 439 (M+H).Anal. Calcd. for C₂₈H₃₀N₄O.3.9HBr.3.1H₂O: C, 41.52; H, 4.99; N, 6.92;Br, 38.47. Found: C, 41.55; H, 4.88; N, 6.73; Br, 38.42.

Example 30 AMD8742: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(phenylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0242] Using general procedure A:N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(143 mg, 0.32 mmol), N-(t-butyloxycarbony)-N-benzylaminoacetaldehyde(150 mg, 0.60 mmol) and sodium cyanoborohydride (50 mg, 0.79 mmol) werereacted in MeOH (3 mL). Evaporation of the solvent and purification ofthe crude material by column chromatography on silica gel (30:70,EtOAc/CH₂Cl₂) gave the desired intermediate (110 mg, 51%) as yellow oil.

[0243] Using general procedure D: the intermediate from above (110 mg,0.16 mmol) was converted to the hydrobromide salt with simultaneousdeprotection of the BOC groups to give AMD8742 (96 mg). ¹H NMR (CD₃OD) δ1.79-1.89 (m, 1H), 2.05-2.09 (m, 1H), 2.13-2.20 (m, 1H), 2.32-2.36 (m,1H), 2.96-2.99 (m, 3H), 3.07-3.16 (m, 1H), 3.25-3.47 (m, 2H), 3.79 (d,1H, J=12.3 Hz), 3.85 (d, 1H, J=12.3 Hz), 4.22 (s, 2H), 4.32-4.35 (b,2H), 4.37-4.44 (b, 3H), 7.41-7.44 (m, 3H), 7.55-7.59 (b, 5H), 7.67-7.70(m 3H), 7.86 (dd, 1H, J=7.8, 7.8 Hz), 7.98-8.00 (m, 1H), 8.31-8.33 (d,1H, J=7.8 Hz), 8.70-8.72 (b, 1H), 8.76 (d, 1H, J=5.7 Hz); ¹³C NMR(CD₃OD) δ 21.26, 21.97, 29.11,46.88, 50.78 (b), 52.31, 52.73, 56.37,60.40, 126.36 (b), 126.94, 130.64, 131.15, 131.82, 132.17, 132.59,140.58, 141.48, 141.60, 141.65 (b), 148.71, 149.23 (b), 151.29 (b),153.39. ES-MS m/z 492.4 (M+H). Anal. Calcd. for C₃₂H₃₇N₅.4.0HBr.3.0H₂O:C, 44.21; H, 5.45; N, 8.06; Br, 36.76. Found: C, 44.33; H, 5.54; N,7.95; Br, 36.89.

Example 31 AMD8743: Preparation ofN-(2-pyridinylmethyl)-N′-(2-aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0244] Using general procedure A:N-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(179 mg, 0.39 mmol), N-Boc-aminoacetaldehyde (120 mg, 0.75 mmol) andsodium cyanoborohydride (55 mg, 0.88 mmol) were reacted in MeOH (3 mL).Evaporation of the solvent and purification of the crude material bycolumn chromatography on silica gel (1.5×20 cm, 30:70 EtOAc/CH₂Cl₂) gavethe desired intermediate (200 mg, 85%) as a yellow oil.

[0245] Using general procedure D: the intermediate from above (200 mg,0.33 mmol) was converted to the hydrobromide salt with simultaneousdeprotection of the BOC groups to give AMD8743 (150 mg). ¹H NMR (CD₃OD)δ 1.81-1.87 (m, 1H), 2.02-2.21 (m, 2H), 2.33-2.37 (m, 1H), 2.87-3.17 (m,5H), 3.23-3.28 (m, 1H), 3.78-3.83 (d, 1H, J=13.5 Hz), 3.87-3.92 (d, 1H,J=13.5 Hz), 4.42 (s, 2H), 4.42-4.44 (m, 1H), 4.60-4.63 (m, 2H), 7.57 (d,2H, J=7.8 Hz), 7.70 (d, 2H, J=7.8), 7.85-7.98 (m, 3H), 8.33 (dd, 2H,J=1.2, 8.1 Hz), 8.79-8.81 (m, 2H); ¹³C NMR (CD₃OD) δ 19.24, 20.00,27.18, 37.29, 50.66, 54.34, 58.34, 124.95, 125.82 (b), 129.50, 130.17,130.37, 138.71, 139.66, 145.00 (b), 146.72, 151.44; ES-MS m/z 402.3(M+H); Anal. Calcd. for C₂₅H₃₁N₅.4.3HBr.2.6H₂O: C, 37.71; H, 5.13; N,8.79; Br, 43.15. Found: C, 37.80; H, 5.03; N, 8.61; Br, 43.11.

Example 32 AMD8753: Preparation ofN-(2-pyridinylmethyl)-N′-3-pyrrolidinyl-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0246] To the solution ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(195 mg, 0.43 mmol) and N-Boc-3-pyrrolidone (91 mg, 0.49 mmol) inmethanol (3 ml) was added trimethylorthoformate (2 ml) and three dropsof acetic acid, at room temperature. This mixture was allowed to stirfor 30 min. at room temperature and sodium cyanoborohydride (130 mg,2.09 mmol) was added. Stirring was continued for a further 18 hours atroom temperature and then the reaction mixture was concentrated. Theresidue was dissolved in ethylacetate (300 mL), and washed withsaturated aqueous NaHCO₃ and brine, then dried (Na₂SO₄) and evaporated.Purification of the residue by column chromatography on silica gel(1.5×20 cm, 50:50 EtOAc/CH₂Cl₂) gave the desired product (120 mg, 45%)as a mixture of diastereomers.

[0247] Using general procedure D: the intermediate from above (120 mg,0.19 mmol) was converted to the hydrobromide salt with simultaneousdeprotection of the BOC groups to give AMD8753 (45 mg) as a mixture ofdiastereomers. ¹H NMR (D₂O) δ 1.73-1.83 (m, 1H), 2.13-2.21 (m, 2H),2.28-2.49 (m, 3H), 2.91 (b, 2H), 3.26-3.69 (m, 4H), 3.83-4.02 (m, 3H),4.33 (s, 2H), 4.33-4.54 (m, 1H), 4.64 (s, 2H), 7.38 (d, 2H, J=7.8 Hz),7.50 (d, 2H, J=7.8), 7.67-7.70 (b, 1H), 7.79-7.84 (b, 2H), 8.15-8.18 (b,1H), 8.25-8.28 (b, 1H), 8.37-8.39 (b, 1H), 8.72-8.74 (b, 1H); ¹³C NMR(D₂O) δ 20.76, 21.96, 27.58, 28.77, 44.80, 45.18, 46.72 (b), 47.79,49.08, 50.34, 50.60, 51.28, 58.11, 58.61, 61.00 (b), 125.37, 126.60,129.95, 130.67, 138.97, 139.79, 139.99, 144.20(b), 146.98(b), 147.36,152.48; ES-MS m/z 428.20 (M+H); Anal. Calcd. forC₂₇H₃₃N₅.3.8HBr.2H₂O.0.4C₂H₄O₂: C, 42.00; H, 5.37; N, 8.81; Br, 38.19.Found: C, 42.10; H, 5.47; N, 8.76; Br, 37.97.

Example 33 AMD8754: Preparation ofN-(2-pyridinylmethyl)-N′-4-piperidinyl-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0248] Reaction ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(215 mg, 0.47 mmol), N-Boc-4-piperidone (188 mg, 0.94 mmol) and sodiumcyanoborohydride (119 mg, 1.89 mmol) in a mixture of methanol (3 ml),trimethylorthoformate (2 ml) and three drops of acetic acid, followed byevaporation of the solvent and purification of the residue by columnchromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH₂Cl₂) gave thedesired intermediate (205 mg, 67%) as a yellow oil.

[0249] Using general procedure D: the intermediate from above (205 mg,0.32 mmol) was converted to the hydrobromide salt with simultaneousdeprotection of the BOC groups to give AMD8754 (120 mg). ¹H NMR (D₂O) δ1.85-1.88 (m, 1H), 1.92-2.05 (m, 2H), 2.08-2.26 (m, 2H), 2.30-2.34 (m,2H), 2.50 (d, 1H, J=13.8 Hz), 2.91-2.93 (m, 2H), 3.06 (t, 2H, J=12.3Hz), 3.23 (t, 1H, J=11.4 Hz), 3.58 (t, 2H, J=14.9 Hz), 3.97 (d, 1H,J=13.8 Hz), 4.03 (d, 1H, J=13.8 Hz), 4.32 (s, 2H), 4.44-4.47 (m 3H),7.38 (d, 2H, J=7.8 Hz), 7.46 (d, 2H, J=7.8 Hz), 7.62-7.72 (m, 3H), 8.10(d, 1H, J=7.8 Hz), 8.12-8.16 (m, 1H), 8.39 (d, 1H, J=5.4 Hz), 8.68 (m,1H); ¹³C NMR (D₂O) δ 20.97, 24.08, 27.01, 27.48, 28.13, 44.42, 49.71,50.32, 51.08, 57.31, 57.72, 125.22, 125.92, 130.03, 130.63, 130.72,139.27, 139.49, 139.66, 142.50, 146.61, 147.50, 153.20; ES-MS m/z 442.2(M+H); Anal. Calcd. for C₂₈H₃₅N₅.3.8HBr.3.8H₂O: C, 42.06; H, 5.60; N,8.76; Br, 37.98. Found: C, 42.20; H, 5.57; N, 8.59; Br, 37.76.

Example 34 AMD8784: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(phenyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0250] Reaction ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(174 mg, 0.38 mmol), 2-[N-(t-butyloxycarbonyl)-N-phenyl]acetaldehyde(165 mg, 0.66 mmol) and sodium cyanoborohydride (70 mg, 1.11 mmol) inMeOH (4 mL) followed by evaporation of the solvent and purification ofthe residue by column chromatography on silica gel (1.5×20 cm, 30:70EtOAc/CH₂Cl₂) gave the desired product (220 mg, 86%) as a yellow oil.

[0251] Using general procedure D: the intermediate from above (220 mg,0.32 mmol) was converted to the hydrobromide salt with simultaneousdeprotection of the BOC groups to give AMD8784 (120 mg). ¹H NMR (D₂O) δ1.73-1.83 (m, 1H), 2.00-2.16 (m, 2H), 2.30-2.34 (m, 1H), 2.91-3.04 (m,3H), 3.16-3.24 (m, 1H), 3.51-3.59 (m, 2H), 3.78 (d, 1H, J=13.5 Hz), 3.85(d, 1H, J=13.5 Hz), 4.32 (s, 2H), 4.39 (s, 2H), 4.39-4.44 (m, 1H), 7.16(d, 2H, J=6.9 Hz), 7.36-7.44 (m, 7H), 7.63-7.71 (m, 3H), 8.09-8.17 (m,2H), 8.44 (d, 1H, J=4.5 Hz), 8.64 (d, 1H, J=6.0 Hz); ¹³C NMR (D₂O) δ20.11, 20.44, 27.65,47.49, 48.20, 49.48, 51.14, 54.71, 59.89, 121.59,125.54, 126.00, 126.15, 128.88, 130.10, 130.70, 130.91, 135.96, 138.46,139.89, 140.24, 142.17, 146.60, 147.65, 148.55, 151.37; ES-MS m/z 478.3(M+H); Anal. Calcd. for C₃₁H₃₅N₅.3.4HBr.2.8H₂O: C, 46.36; H, 5.52; N,8.72; Br, 33.82. Found: C, 46.15; H, 5.30; N, 8.55; Br, 34.11.

[0252] General Procedure G: Reductive Amination Using TrimethylOrthoformate

[0253] To a stirred solution of the amine (1 equivalent) in anhydrousmethanol (concentration ˜0.1 M), at room temperature, was added thecarbonyl compound (1.4 equiv.), trimethyl orthoformate (one half thevolume of methanol), and a catalytic amount of acetic acid. Once thecarbonyl had dissolved (˜30 minutes), NaBH₃CN (3.9 equiv.) was added inone portion and the resultant solution was stirred at room temperaturefor the indicated time. The solvent was removed under reduced pressureand CH₂Cl₂ (20 mL/mmol of amine) and aqueous NaHCO₃ (10 mL/mmol amine)solution was added to the residue. The phases were separated and theaqueous phase was extracted with CH₂Cl₂ (3×10 mL/mmol amine). Thecombined organic phases were dried (Na₂SO₄) and concentrated. The crudematerial was purified by chromatography.

[0254] General Procedure H: Enamide Formation

[0255] To a stirred solution of the carbonyl compound (1 equivalent) inanhydrous toluene (concentration ˜0.3 M), at room temperature, was addedthe amide (2-3 equiv.), Amberlyst 15 (50% weight of the carbonylcompound), and 4 Å molecular sieves. The resultant solution was heatedup to reflux for the indicated time. The mixture was filtered and theresin was washed with toluene (6 mL/mmol carbonyl compound). Thecombined solution was heated to 60° C. and 1% aqueous NaHCO₃ (12 mL/mmolcarbonyl compound) solution was added to the residue. The phases wereseparated and the organic phase was dried (Na₂SO₄) and concentrated. Thecrude material was purified by chromatography.

[0256] General Procedure I: Alkylation Reaction2-[(2-nitrobenzenesulfonylamino)methyl]pyridine with benzylic bromides.

[0257] To a stirred solution of the bromide (1 equiv.) in anhydrous MeCN(concentration ˜0.1 M), at room temperature, was added the2-[(2-nitrobenzenesulfonylamino)methyl]pyridine (1-1.2 equiv.), K₂CO₃ (2equiv.). The resultant solution was stirred at 60° C. under a nitrogenatmosphere for the indicated time. The solvent was removed under reducedpressure and CH₂Cl₂ (100 mL/mmol amide) was added to the residue. Thesolution was filtered through celite, and concentrated in vacuo. Thecrude material was purified by chromatography.

Example 35 AMD8759: Preparation ofN-(2-pyridinylmethyl)-N′-(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine

[0258] Using General Procedure G: 7-methoxy-2-tetralone (60 mg, 0.34mmol),N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine(100 mg, 0.24 mmol) and NaBH₃CN (59 mg, 0.94 mmol) in MeOH (3 mL),trimethyl orthoformate (1.7 mL) and acetic acid (3 drops) were reactedfor 3.5 hours. Following work-up, the crude material was purified bychromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH 98:1:1) to give thedesired product (71 mg, 52%) as a yellow foam.

[0259] Using general Procedure D: the foam from above (65 mg, 0.11 mmol)was reacted with thiophenol (35 μL, 0.34 mmol) and K₂CO₃ (78 mg, 0.57mmol) in DMF (1.1 mL). The crude product was purified by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH 23:1:1) togive AMD8759 (25 mg, 57%) as a yellow oil. ¹H NMR (CDCl₃) δ 1.64-1.68(m, 1H), 1.95 (s, 2H), 2.05-2.09 (m, 1H), 2.64-2.83 (m, 3H), 2.96-3.05(m, 2H), 3.77 (s, 3H), 3.83 (s, 2H), 3.89 (s, 2H), 3.92 (s, 2H), 6.62(s, 1H), 6.67-6.70 (m, 1H), 6.99 (d, 2H, J=8.3 Hz), 7.16-7.18 (m, 1H),7.26-7.32 (m, 4H), 7.61-7.64 (m, 1H), 8.56 (d, 1H, J=4.5 Hz); ¹³C NMR(CDCl₃) δ 27.49, 30.11, 37.36, 51.24, 53.07, 53.62, 54.89, 55.65,112.53, 114.27, 122.31, 122.73, 128.61 (2 carbons), 128.78 (2 carbons),129.89, 136.79 (2 carbons), 139.27, 139.63, 149.71(2 carbons), 157.97,160.17. ES-MS m/z 388 (M+H). Anal. Calcd. for C₂₅H₂₉N₃O.0.4H₂O: C,76.07; H, 7.61; N, 10.65. Found: C, 76.09; H, 7.62; N, 10.55.

Example 36 AMD8762: Preparation ofN-(2-pyridinylmethyl)-N′-(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine

[0260] Using General Procedure G: 6-methoxy-2-tetralone (112 mg, 0.63mmol),N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine(186 mg, 0.45 mmol) and NaBH₃CN (110 mg, 1.76 mmol) in a mixture of MeOH(5 mL), trimethyl orthoformate (2.8 mL) and acetic acid (5 drops) werereacted for 3.5 hours. Purification of the crude material bychromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH 98:1:1) gave the desiredproduct (102 mg, 40%) as a yellow foam.

[0261] Using General Procedure C: the intermediate from above (102 mg,0.18 mmol) was reacted with thiophenol (54 μL, 0.53 mmol) and K₂CO₃ (122mg, 0.89 mmol) in DMF (1.7 mL) and the crude material was purified byradial chromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH98:1:1) to give AMD8762 (51 mg, 74%) as a yellow oil. ¹H NMR (CDCl₃) δ1.63-1.67 (m, 1H), 1.83 (s, 2H), 2.04-2.08 (m, 1H), 2.57-2.62 (m, 1H),2.79-3.00 (m, 4H), 3.78 (s, 3H), 3.83 (s, 2H), 3.89 (s, 2H), 3.92 (s,2H), 6.62 (s, 1H), 6.63-6.67 (m, 2H), 6.99 (d, 2H, J=8.4 Hz), 7.15-7.17(m, 1H), 7.32 (s, 3H), 7.61-7.63 (m, 1H), 8.56 (d, 1H, J=4.2 Hz); ¹³CNMR (CDCl₃) δ 28.25, 29.47, 35.90, 50.86, 52.92, 53.22, 54.49, 55.22,112.03, 113.25, 121.89, 122.32, 127.37, 128.19 (2 carbons), 128.36 (2carbons), 130.15, 136.38, 137.34, 138.84, 139.33, 149.30, 157.66,159.79. ES-MS m/z 388 (M+H). Anal. Calcd. for C₂₅H₂₉N₃O.0.4H₂O: C,76.07; H, 7.61; N, 10.65. Found: C, 76.14; H, 7.55; N, 10.64.

Example 37 AMD8770: Preparation ofN-(2-pyridinylmethyl)-N′-(1-methyl-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine

[0262] Using General Procedure G: 1-methyl-2-tetralone (109 mg, 0.68mmol),N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine(200 mg, 0.48 mmol) and NaBH₃CN (118 mg, 1.87 mmol) were reacted in amixture of MeOH (5 mL), trimethyl orthoformate (2.8 mL) and acetic acid(5 drops) for 48.5 hours. Purification of the crude material by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH 98:1:1) gave the product(41 mg, 15%) as a yellow foam.

[0263] Using General Procedure C: the intermediate from above (65 mg,0.12 mmol) was reacted with thiophenol (36 μL, 0.35 mmol) and K₂CO₃ (81mg, 0.59 mmol) in DMF (1.2 mL). The crude product was purified by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH 23:1:1) togive AMD8770 (25 mg, 57%) as a yellow oil. ¹H NMR (CDCl₃) δ 1.22 (d, 3H,J=7.2 Hz), 1.30 (d, 1H, J=6.6 Hz), 179-1.86 (m, 3H), 2.84-2.90 (m, 2H),2.99-3.06 (m, 2H), 3.11-3.15 (m, 1H), 3.84 (s, 4H), 3.91 (s, 2H),7.09-7.18 (m, 6H), 7.26-7.33 (m, 4H), 7.63-7.64 (m, 1H), 8.56 (d, 1H,J=4.5 Hz); ¹³C NMR (CDCl₃) δ 17.30, 24.77, 29.05, 36.82, 51.16, 53.66,54.91, 56.00, 122.35, 122.77, 126.06, 126.20, 128.63 (2 carbons), 128.79(2 carbons), 129.18, 129.85, 135.96, 136.83, 139.23, 139.82, 142.28,149.74, 160.19. ES-MS m/z 372 (M+H). Anal. Calcd. for C₂₅H₂₉N₃.0.4H₂O:C, 79.28; H, 7.93; N, 11.09. Found: C, 79.42, H, 7.99; N, 10.70.

Example 38 AMD8790: Preparation ofN-(2-pyridinylmethyl)-N′-(7-methoxy-3,4-dihydronaphthalenyl)-1-(aminomethyl)-4-benzamide

[0264] Using General Procedure H: 7-methoxy-2-tetralone (300 mg, 1.71mmol) and α-bromo-p-toluic amide (732 mg, 3.42 mmol) in toluene (8 mL)containing Amberlyst 15 (150 mg) and 4 Å molecular sieve (600 mg) werereacted for for 24 hours. Purification of the crude material by columnchromatography on silica gel (CH₂Cl₂) and recrystallisation (EtOAc) gavethe desired product (90 mg, 14%) as yellow crystals.

[0265] Using General Procedure 1: Reaction of the intermediate fromabove (90 mg, 0.24 mmol) with2-[2-nitrobenzenesulfonylamino)methyl]pyridine (85 mg, 0.29 mmol) andK₂CO₃ (66 mg, 0.48 mmol) in MeCN (3 mL) for 24 hours, followed bypurification of the crude material by column chromatography on silicagel (CH₂Cl₂:/MeOH 99:1) gave the desired product (85 mg, 61%) as ayellow foam.

[0266] Using general procedure C: Reaction of the foam (65 mg, 0.12mmol) with thiophenol (45 μL, 0.44 mmol) and K₂CO₃ (100 mg, 0.73 mmol)in DMF (1.5 mL) followed by purification of the crude material by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH 24:1) gave AMD8790(31 mg, 53%) as a yellow oil. ¹H NMR (CD₃OD) δ 2.57 (t, 2H, J=7.9 Hz),2.81 (t, 2H, J=6.5 Hz), 3.74 (s, 3H), 3.85 (s, 2H), 3.85 (s, 2H), 6.60(s, 1H), 6.61-6.62 (m, 1H), 6.98 (d, 1H, J=8.7 Hz), 7.13 (s, 1H),7.31-7.33 (m, 1H), 7.46-7.49 (m, 3H), 7.78-7.85 (m, 3H), 8.50 (br s,1H); ¹³C NMR (CDCl₃) δ 28.47, 28.66, 53.89, 54.96, 56.04, 112.45,113.03, 114.54, 124.23 (2 carbons), 124.58 (2 carbons), 127.02, 129.21(2 carbons), 130.04 (2 carbons), 135.51, 137.54, 138.62, 139.15, 145.08,150.26, 160.40, 169.12. ES-MS m/z 400 (M+H). Anal. Calcd. forC₂₅H₂₅N₃O₂.0.5H₂O: C, 73.51; H, 6.42; N, 10.29. Found: C, 73.48, H,6.42; N, 9.89.

Example 39 AMD8805: Preparation ofN-(2-pyridinylmethyl)-N′-(6-methoxy-3,4-dihydronaphthalenyl)-1-(aminomethyl)-4-benzamide

[0267] Using general procedure H: 6-methoxy-2-tetralone (300 mg, 1.71mmol) and α-bromo-p-toluic amide (1.1 g, 5.11 mmol) in toluene (15 mL)containing Amberlyst 15 (150 mg) and 4 Å molecular sieve (1 g) werereacted for 24 hours. Purification of the crude material by columnchromatography on silica gel (CH₂Cl₂) gave the desired product (237 mg,38%) as yellow crystal.

[0268] Using general procedure I: the intermediate from above (237 mg,0.64 mmol) was reacted with2-[(2-nitrobenzenesulfonylamino)methyl]pyridine (186 mg, 0.64 mmol) andK₂CO₃ (177 mg, 1.28 mmol) in MeCN (6.6 mL) for 24 hours. The crudematerial was purified by column chromatography on silica gel(EtOAc/Hexane 7:3) to give the desired product (310 mg, 83%) as a yellowfoam.

[0269] Using general procedure C: The foam (310 mg, 0.53 mmol) wasreacted with thiophenol (163 μL, 1.59 mmol) and K₂CO₃ (366 mg, 2.65mmol) in DMF (5.3 mL). Purification of the crude material by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH 24:1) affordedAMD8805 (170 mg, 81%) as a yellow oil. ¹H NMR (CD₃OD) δ 2.58 (t, 2H,J=8.0 Hz), 2.88 (t, 2H, J=8.0 Hz), 3.77 (s, 3H), 3.87 (s, 2H), 3.90 (s,2H), 6.68-6.70 (m, 1H), 6.70 (s, 1H), 6.94 (d, 1H, J=8.4 Hz), 7.05 (s,1H), 7.20-7.25 (m, 1H), 7.48-7.50 (m, 3H), 7.83-7.86 (m, 3H), 8.50 (d,1H, J=4.2 Hz); ¹³C NMR (CDCl₃) δ 28.47, 28.66, 48.87, 50.91, 54.54,120.31, 125.88, 126.28, 126.41 (2 carbons), 127.57, 128.29, 129.45 (2carbons), 130.80 (2 carbons), 131.74 (2 carbons), 131.92, 132.10,134.36, 142.97, 147.00, 147.86, 169.12. ES-MS m/z 400 (M+H). Anal.Calcd. for C₂₅H₂₅N₃O₂.0.6H₂O: C, 73.18; H, 6.44; N, 10.24. Found: C,73.33, H, 6.41; N, 10.27.

Example 40 AMD8902: Preparation ofN-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine

[0270] Using general procedure G: Reaction of 7-methoxy-2-tetralone (299mg, 1.70 mmol) andN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine(500 mg, 1.21 mmol) with NaBH₃CN (296 mg, 4.72 mmol) in a mixture ofMeOH (15 mL), trimethyl orthoformate (8.5 mL) and acetic acid (15 drops)for 3.5 hours followed by purification of the crude material by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH 98:1:1) gave the desiredproduct (520 mg, 75%) as a yellow foam.

[0271] The intermediate from above was reacted in a similar manner with2-imidazole-carboxaldehyde and the corresponding imidazole intermediate(65 mg, 0.11 mmol) was deprotected (general procedure C) by reaction-with thiophenol (35 μL, 0.34 mmol) and K₂CO₃ (78 mg, 0.57 mmol) in DMF(1.1 mL). Purification of the crude material by radial chromatography onsilica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH 23:1:1) afforded AMD8902 (25mg, 57%) as a yellow foam. ¹H NMR (CDCl₃) δ 1.64-1.68 (m, 1H), 1.95 (s,2H), 2.05-2.09 (m, 1H), 2.64-2.83 (m, 3H), 2.96-3.05 (m, 2H), 3.77 (s,3H), 3.83 (s, 2H), 3.89 (s, 2H), 3.92 (s, 2H), 6.62 (s, 1H), 6.67-6.70(m, 1H), 6.99 (d, 2H, J=8.3 Hz), 7.16-7.18 (m, 1H), 7.26-7.32 (m, 4H),7.61-7.64 (m, 1H), 8.56 (d, 1H, J=4.5 Hz); ¹³C NMR (CDCl₃) δ 27.49,30.11, 37.36, 51.24, 53.07, 53.62, 54.89, 55.65, 112.53, 114.27, 122.31,122.73, 128.61 (2 carbons), 128.78 (2 carbons), 129.89, 136.79 (2carbons), 139.27, 139.63, 149.71(2 carbons), 157.97, 160.17. ES-MS m/z388 (M+H). Anal. Calcd. for C₂₅H₂₉N₃O.0.4H₂O: C, 76.07; H, 7.61; N,10.65. Found: C, 76.09; H, 7.62; N, 10.55.

Example 41 AMD8863: Preparation ofN-(2-pyridinylmethyl)-N′-(8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine

[0272] Following the procedure of Manitto, P.; Speranza, G.; Monti, D.;Fontana, G. and Panosetti, E. (Tetrahedron Lett. 1995, 51, 11531-11546):8-hydroxy-2-tetralone was prepared from 7-methoxy-1-tetralone.

[0273]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine.

[0274] Using General Procedure B: Reaction of 8-hydroxy-2-tetralone (110mg, 0.68 mmol),N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine(280 mg, 0.68 mmol) and NaBH(OAc)₃ (287 mg, 1.4 mmol) in a mixture ofCH₂Cl₂ (10 mL) and acetic acid (0.2 mL) for 18 hours gave, afterwork-up, ˜400 mg (quant. yield) of the title compound as a yellow foam.

[0275] Using general procedure C: the crude product from above (100 mg,0.18 mmol) was reacted with thiophenol (46 μL, 0.45 mmol) and K₂CO₃ (75mg, 0.54 mmol) in DMF (2 mL). Purification of the crude material byradial chromatography on silica gel (1 mm plate, CHCl₃/MeOH/NH₄OH20:2:1) afforded AMD8863 (35 mg, 52%) as a white solid. ¹H NMR (CDCl₃) δ1.59-1.66 (m, 1H), 2.01-2.05 (m, 1H), 2.38 (dd, 1H, J=16, 9 Hz),2.77-3.08 (m, 4H), 3.82 (s, 2H), 3.91 (s, 2H), 3.93 (s, 2H), 6.47 (d,1H, J=8 Hz), 6.60 (d, 1H, J=8 Hz), 6.89 (t, 1H, J=8 Hz), 7.17-7.21 (m,1H), 7.29 (br s, 4H), 7.35 (d, 1H, J=8 Hz), 7.66 (dt, 1H, J=8, 1 Hz),8.56 (br d, 1H, J=5 Hz); ¹³C NMR (CDCl₃) δ 28.3, 29.4, 30.4, 50.9, 52.9,53.1, 53.9, 111.8, 119.8, 122.2, 122.8, 125.9, 128.3, 128.5, 136.8,137.7, 138.3, 139.2, 148.9, 154.8, 159.3; ES-MS m/z 374 (M+H). Anal.Calcd. for C₂₄H₂₇N₃O.0.3H₂O: C, 76.19; H, 7.34; N, 11.11. Found: C,76.21; H, 7.24; N, 10.96.

Example 42 AMD 8886: Preparation ofN-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine

[0276] Using General Procedure B: Reaction ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine (400 mg, 0.72 mmol), imidazole-2-carboxaldehyde (138 mg,1.4 mmol) and NaBH(OAc)₃ (457 mg, 2.2 mmol) in a mixture of CH₂Cl₂ (20mL) and acetic acid (0.5 mL) for 48 hours, followed by purification ofthe crude material by radial chromatography on silica gel (4 mm plate,CHCl₃/MeOH/NH₄OH 20:1:1) afforded the desired intermediate (175 mg, 41%)as a yellow/green foam.

[0277] Using general procedure C: the intermediate from above (175 mg,0.28 mmol) was reacted with thiophenol (71 μL, 0.68 mmol), and K₂CO₃(114 mg, 0.81 mmol) in DMF (3 mL). The crude material was purified byradial chromatography on silica gel (1 mm plate, CHCl₃/MeOH/NH₄OH20:2:1) to give AMD8886 (53 mg, 43%) as a white foam. ¹H NMR (CDCl₃) δ1.62-1.76 (m, 1H), 1.96-2.05 (m, 1H), 2.53-2.66 (m, 1H), 2.70-2.79 (m,2H), 2.96-3.07 (m, 2H), 3.48 (s, 2H), 3.70 (br s, 2H), 3.79-3.82 (m,3H), 3.84-3.95 (m, 3H), 6.53-6.62 (m, 2H), 6.88 (t, 1H, J=8 Hz), 6.93(s, 2H), 7.15-7.19 (m, 1H), 7.24-7.33 (m, 6H), 7.64 (dt, 1H, J=8, 2 Hz),8.55 (br d, 1H, J=5 Hz); ¹³C NMR (CDCl₃) δ 25.0, 25.9, 30.0, 47.3, 53.1,54.1, 54.2, 56.4, 111.9, 119.3, 122.1, 122.6, 123.4, 126.0, 128.4,128.7, 136.6, 137.5, 138.5, 138.7, 147.9, 149.1, 155.6, 159.3. ES-MS m/z454 (M+H). Anal. Calcd. for C₂₈H₃₁N₅O.0.9H₂O: C, 71.59; H, 7.04; N,14.91. Found: C, 71.58; H, 6.76; N, 14.70.

Example 43 AMD8 889: Preparation ofN-(2-pyridinylmethyl)-N′-(8-Fluoro-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine

[0278] Following the procedure of Nixon, J. A.; Pioch, R. P.; Schaus, J.M.; and Titus, R. D. (EP-A-0 343 830, Eli Lilly and Company):8-fluoro-2-tetralone was prepared from o-fluorophenylacetic acid.

[0279]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(8-Fluoro-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine.

[0280] Following General Procedure B: Reaction of 8-fluoro-2-tetralone(159 mg, 0.97 mmol),N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine(400 mg, 0.97 mmol) and NaBH(OAc)₃ (411 mg, 1.9 mmol) in a mixture ofCH₂Cl₂ (10 mL) and acetic acid (0.2 mL) for 18 hours followed bypurification of the crude material by column chromatography on silicagel (CHCl₃/MeOH/NH₄OH 20:2:1) afforded the title compound (500 mg, 92%)as a yellow foam.

[0281] Using general procedure C: the intermediate from above (130 mg,0.23 mmol) was reacted with thiophenol (60 μL, 0.58 mmol) and K₂CO₃ (96mg, 0.70 mmol) in DMF (2 mL). Purification of the crude material byradial chromatography on silica gel (1 mm plate, CHCl₃/MeOH/NH₄OH20:2:1) afforded AMD8889 (46 mg, 43%) as a white foam. ¹H NMR (CDCl₃) δ1.58-1.71 (m, 1H), 1.72-1.95 (br s, 2H), 2.00-2.09 (m, 1H), 2.48 (dd,1H, J=17, 9 Hz), 2.73-3.00 (m, 3H), 3.11 (dd, 1H, J=17, 5 Hz), 3.83 (s,2H), 3.90 (s, 2H), 3.92 (s, 2H), 6.79-6.88 (m, 2H), 7.02-7.07 (m, 1H),7.14-7.18 (m, 1H), 7.29-7.39 (m, 5H), 7.63 (dt, 1H, J=15, 2), 8.55-8.57(m, 1H); ¹³C NMR (CDCl₃) δ 27.6, 28.9, 29.2, 50.7, 51.8, 53.1, 54.4,111.8 (d, ²J_(C-F)=22 Hz), 121.8, 122.3, 122.7, 123.9, 126.4 (d,³J_(C-F)=9 Hz), 128.1, 128.3, 136.3, 139.0 (d, ²J_(C-F)=22 Hz), 149.2,159.7, 161.0 (d, J_(C-F)=244 Hz). ES-MS m/z 376 (M+H). Anal. Calcd. forC₂₄H₂₆N₃F.0.1H₂O: C, 76.40; H, 7.00; N, 11.14. Found: C, 76.35; H, 7.02;N, 11.14.

Example 44 AMD8895: Preparation ofN-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(8-Fluoro-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine

[0282] Using general procedure B: Reaction ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(8-Fluoro-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine(450 mg, 0.81 mmol), imidazole-2-carboxaldehyde (155 mg, 1.6 mmol) andNaBH(OAc)₃ (512 mg, 2.4 mmol) in a mixture of CH₂Cl₂ (10 mL) and aceticacid (1.0 mL) for 72 hours, followed by purification of the crudematerial by column chromatography on silica gel (CHCl₃/MeOH/NH₄OH20:2:1) gave 400 mg (˜80% recovery) of a ˜1:1 mixture of startingmaterial and product as a yellow foam.

[0283] Using general procedure C: the mixture from above (370 mg, ˜0.58mmol) was reacted with thiophenol (150 μL, 1.5 mmol) and K₂CO₃ (240 mg,1.7 mmol) in DMF (3 mL). Purification of the crude material by radialchromatography on silica gel (1 mm plate, CHCl₃/MeOH/NH₄OH 20:1:1)afforded AMD8895 (57 mg, 22%) as a white foam. ¹H NMR (CDCl₃) δ1.59-1.72 (m, 1H), 2.10-2.16 (m, 1H), 2.64-2.80 (m, 2H), 2.88-3.05 (m,3H), 3.76 (d, 1H, J=14 Hz), 3.79 (d, 1H, J=14 Hz), 3.81 (s, 2H), 3.86(s, 2H), 3.92 (s, 2H), 6.77-6.84 (m, 2H), 6.94 (s, 2H), 7.02-7.07 (m,1H), 7.15 (dd, 1H, J=7, 6 Hz), 7.27-7.31 (m, 6H), 7.63 (dt, 1H, J=8, 2Hz), 8.55 (br d, 1H, J=4 Hz); ¹³C NMR (CDCl₃) δ 24.3, 25.2, 29.6, 47.8,53.1, 54.3, 54.5, 55.4, 111.8 (d, ²J_(C-F)=22 Hz), 121.9, 122.3, 123.3,123.5, 123.9, 126.5 (d, ³J_(C-F)=9 Hz), 128.4, 128.5, 136.4, 138.2,138.7, 138.9 (d, ²J_(C-F)=25 Hz), 147.4, 149.3, 159.6, 161.0 (d,²J_(C-F)=244 Hz). ES-MS m/z 456 (M+H). Anal. Calcd. forC₂₉H₃₀N₅F.0.3H₂O: C, 72.95; H, 6.69; N, 15.19. Found: C, 72.99; H, 6.86;N, 15.06.

Example 45 AMD8852: Preparation ofN-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0284] 7-Amino-5,6,7,8-tetrahydroquinoline was prepared by the method ofI. A. Cliffe et al. Tetrahedron letters 1991, 32, 6789-6792.

[0285]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine.

[0286] Using General procedure B: Reaction of7-amino-5,6,7,8-tetrahydroquinoline (72 mg, 0.47 mmol) andnosyl-protected Trevor aldehyde (200 mg, 0.49 mmol) and NaBH(OAc)₃ (206mg, 0.98 mmol) in CH₂Cl₂ (5 mL) for 18 hours gave, after workup, thecrude product (260 mg, 98% yield) as a green foam. This was used withoutfurther purification in the next step.

[0287] Using general procedure C: The crude product from above (100 mg,˜0.18 mmol) was reacted with thiophenol (47 μL, 0.45 mmol) and K₂CO₃ (77mg, 0.54 mmol) in DMF (2 mL). Purification of the crude material byradial chromatography on silica gel (1 mm plate, CHCl₃/MeOH/NH₄OH20:2:1) afforded the corresponding free base (55 mg, 77%) of AMD8852.Using general procedure D: the free base was converted to thehydrobromide salt to give AMD8852 (94 mg, 89%) as a white solid. ¹H NMR(CDCl₃) δ 1.66-1.71 (m, 1H), 1.98 (br s, 2H), 2.02-2.07 (m, 1H),2.73-2.85 (m, 3H), 3.06-3.09 (m, 1H), 3.21 (dd, 1H, J=18, 6 Hz), 3.81(s, 2H), 3.88 (s, 2H), 3.90 (s, 2H), 7.01 (dd, 1H, J=8, 5 Hz), 7.13 (dd,1H, J=7, 5 Hz), 7.26-7.35 (m, 6H), 7.61 (dt, 1H, J=8, 2 Hz), 8.33-8.34(m, 1H), 8.53 (br d, 1H, J=5 Hz); ¹³C NMR (CDCl₃) δ 26.4, 28.7, 39.6,50.7, 52.1, 53.1, 54.4, 121.0, 121.8, 122.3, 128.1, 128.3, 131.4, 136.2,136.3, 138.8, 139.0, 147.0, 149.2, 155.6, 159.6. ES-MS m/z 359 (M+H).Anal. Calcd. for C₂₃H₂₆N₄.4.1HBr.0.6H₂O.0.7C₂H₄O₂: C, 39.44; H, 4.62; N,7.51; Br, 44.01. Found: C, 39.46; H, 4.80; N, 7.46; Br, 44.03.

Example 46 AMD8858:N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0288] Using general procedure B: Reaction ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine(175 mg, 0.32 mmol), imidazole-2-carboxaldehyde (155 mg, 1.6 mmol) andNaBH(OAc)₃ (137 mg, 0.64 mmol) in MeOH (3 mL) for 8 hours at 60° C.,followed by purification of the crude material by column chromatographyon silica gel (CHCl₃/MeOH/NH₄OH 20:2:1) gave the desired product (169mg, 84%) as a yellow/green foam.

[0289] Using general procedure C: the intermediate from above (169 mg,0.27 mmol) was was reacted with thiophenol (70 μL, 0.68 mmol) and K₂CO₃(113 mg, 0.81 mmol) in DMF (3 mL). Purification of the crude material byradial chromatography on silica gel (1 mm plate, CHCl₃/MeOH/NH₄OH20:2:1) afforded the free base (30 mg, 25%) which was subsequentlyconverted to the hydrobromide salt using general procedure X to giveAMD8858 (35 mg, 58%) as a white solid. ¹H NMR (CDCl₃) δ 1.66-1.70 (m,1H), 2.14-2.19 (M, 1H), 2.26 (br s, 1H), 2.66-2.83 (m, 2H), 3.01-3.12(m, 3H), 3.64 (d, 1H, J=15 Hz), 3.77-3.82 (m, 3H), 3.86 (s, 2H), 3.90(s, 2H), 6.92 (s, 2H), 7.01-7.03 (m, 1H), 7.17-7.20 (m, 1H), 7.26-7.34(m, 6H), 7.62 (dt, 1H, J=8, 2 Hz), 8.31-8.33 (m, 1H), 8.52-8.54 (m, 1H),9.68 (br s, 1H); ¹³C NMR (CDCl₃) δ 24.2, 28.1, 35.7, 47.8, 53.1, 54.2,55.5, 55.7, 121.1, 121.9, 122.3, 128.4, 128.5, 131.4, 136.3, 136.4,138.2, 139.1, 147.0, 147.3, 149.2, 156.1, 159.6. ES-MS m/z 429 (M+H).Anal. Calcd. for C₂₇H₃₀N₆.5.2HBr.0.2H₂O: C, 37.76; H, 4.23; N, 9.54; Br,46.80. Found: C, 38.02; H, 4.53; N, 9.20; Br, 46.99.

Example 47 AMD8785: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(2-naphthalenylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0290] To a stirred solution of 3-amino-1,2-propanediol (1.50 g, 16.5mmol) in dry MeOH (25 mL) was added 2-naphthaldehyde (1.50 g, 9.6 mmol)followed by sodium cyanoborohydride (1.02 g, 16.2 mmol) and the reactionmixture was stirred for 16 hours. The reaction mixture was concentratedin vacuo, diluted with EtOAc (70 mL) and washed with saturated aqueoussodium bicarbonate (70 mL). The aqueous layer was extracted with EtOAc(2×50 mL) and the combined organic layers were then washed with brine(75 mL), dried (MgSO₄), filtered and concentrated in vacuo. The residuewas used directly in the next step without further purification.

[0291] A solution of the crude amine (900 mg) in THF (20 mL) was treatedwith di-t-butyldicarbonate (1.02 g, 4.68 mmol) for 1 hour. The crudeproduct was purified by column chromatography on silica gel(EtOAc/hexanes, 1:1) to give the BOC-naphthyl-derivatized diol. ¹H NMR(CDCl₃) δ 1.49 (br s, 9H), 3.21-3.49 (m, 4H), 3.53 (br m, 2H), 3.72 (brs, 1H), 4.57-4.68 (br s, 2H), 7.36 (br d, 1H, J=8.1 Hz), 7.47-7.50 (m,2H), 7.64 (s, 1H), 7.79-7.84 (m, 3H).

[0292] To a solution of the diol from above (705 mg, 2.13 mmol) inwater/CH₂Cl₂ (20 mL, 1:1) was added sodium periodate (1.06 g, 4.96 mmol)and the mixture stirred vigourously for 3 hours. The reaction wasdiluted with CH₂Cl₂ (25 mL) and washed with water (25 mL). The organiclayer was dried (Na₂SO₄), filtered and concentrated in vacuo. Theresultant crude aldehyde was used without further purification in thenext step.

[0293] To a solution ofN-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(260 mg, 0.57 mmol) and the crude aldehyde from above in MeOH (15 mL)was added sodium cyanoborohydride (88 mg, 1.4 mmol) and the mixture wasstirred for 16 hours. After work-up, the crude material was purified bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 96:4 to 95:5) to givethe desired intermediate (208 mg, 50%) as a yellow oil.

[0294] Using general procedure D: the oil from above (38 mg, 0.05 mmol)was converted to the hydrobromide salt with simultaneous deprotection ofthe BOC groups to give AMD8785 (37 mg, 83%) as a white solid. ¹H NMR(D₂O) δ 1.67-1.75 (br m, 1H), 1.97-2.12 (br m, 2H), 2.26-2.30 (br m,1H), 2.87-3.04 (m, 4H), 3.14-3.18 (br d, 2H, J=10.5 Hz), 3.58 (s, 2H),3.76 (d, 1H, J=13.2 Hz), 3.91 (d, 1H, J=13.2 Hz), 4.13-4.28 (m, 5H),7.22 (d, 2H, J=8.0 Hz), 7.32 (d, 2H, J=8.0 Hz), 7.40 (d, 1H, J=9.0 Hz),7.45 (d, 1H, J=8.0 Hz), 7.56-7.62 (m, 3H), 7.74 (dd, 1H, J=7.0, 6.0 Hz),7.82 (s, 1H), 7.87-7.92 (m, 3H), 8.04 (t, 1H, J=7.5 Hz), 8.20 (d, 1H,J=8.0 Hz), 8.48 (d, 1H, J=5.0 Hz), 8.58 (d, 1H, J=5.0 Hz); ¹³C NMR (D₂O)δ 19.86, 20.43, 27.72, 45.70, 48.06, 48.80, 50.73, 51.14, 54.94, 59.94,125.69, 126.27, 126.43, 127.01, 127.65, 127.97, 128.11, 128.25, 128.53,129.49, 130.05, 130.13, 130.84 (4 carbons), 133.10, 133.51, 139.12,139.70, 140.49, 142.93, 147.03, 147.65, 147.77, 151.65. ES-MS m/z 542(M+H). Anal. Calcd. for C₃₆H₃₉N₅.4.0HBr.4.4H₂O: C, 45.77; H, 5.53; N,7.41; Br, 33.83. Found: C, 45.68; H, 5.34; N, 7.16; Br, 34.03.

Example 48 AMD8820: Preparation ofN-(2-pyridinylmethyl)-N′-[2-(isobutylamino)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0295] To a stirred solution of sec-butylamine (1.0 mL, 9.90 mmol) inCH₂Cl₂ (40 mL) at room temperature was added triethylamine (2.8 mL, 20.1mmol) and 2-nitrobenzenesulfonyl chloride (2.6 g, 11.7 mmol) as a solidin three portions and the reaction stirred for 16 hours. The mixture wasthen washed with saturated aqueous sodium bicarbonate (40 mL) and brine(40 mL) and the organic phase dried (Na₂SO₄), filtered and concentratedin vacuo to give the nosyl-protected amine as a green solid.

[0296] To a stirred solution of the nosyl sec-butyl amine (850 mg, 3.30mmol) in dry DMF (5 mL) was added 2-bromoethanol (0.40 mL, 5.6 mmol) andpowdered potassium carbonate (910 mg, 6.6 mmol) and the mixture stirredfor 2 days. The reaction was diluted with EtOAc (50 mL) and washed withbrine (4×30 mL) and the combined organic layers dried (MgSO₄), filteredand concentrated in vacuo. Purification of the crude product by columnchromatography on silica gel (EtOAc/hexanes, 1:1) gave the hydroxyethylproduct (188 mg, 19%) as a clear oil. ¹H NMR (CDCl₃) δ 0.82 (t, 3H,J=6.0 Hz), 1.12 (d, 3H, J=6.0 Hz), 1.43-1.56 (m, 2H), 2.27 (br s, 1H),3.40 (t, 2H, J=6.0 Hz), 3.77-3.87 (m, 3H), 7.58-7.61 (m, 1H), 7.67-7.71(m, 2H), 8.04-8.07 (m, 1H).

[0297] Using general procedure F: A solution of this alcohol (308 mg,1.02 mmol) in CH₂Cl₂ (10 mL) was oxidized with Dess-Martin periodinane(600 mg, 1.42 mmol) for 45 min to give the crude aldehyde which was usedwithout further purification.

[0298] To a solution ofN-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(224 mg, 0.49 mmol) and the crude aldehyde from above, in MeOH (7 mL)was added sodium cyanoborohydride (65 mg, 1.04 mmol) and the mixture wasstirred for 17 hours. After work-up, the crude material was purified bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 96:4 to 9:1) to givethe desired intermediate as a yellow oil.

[0299] Using general procedures C and D: the oil from above was reactedwith thiophenol (0.35 mL, 3.4 mmol) and potassium carbonate (555 mg,4.02 mmol) in CH₃CN (5 mL) for 3 hours. Purification of the crudeintermediate by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,95:5:0 followed by 90:9:1) gave the desired BOC-protected intermediate(49 mg, 18% over 2 steps) as a clear oil. Conversion to the hydrobromidesalt with simultaneous deprotection of the BOC group followed byre-precipitation of the crude solid from methanol/ether gave AMD8820 (33mg, 60%) as a white solid. ¹H NMR (D₂O) mixture of diastereomers δ 0.85(d, J=7.3 Hz) and 0.89 (d, J=7.3 Hz) (total 3H), 1.19 (t, 3H, J=6.7 Hz),1.41-1.52 (m, 1H), 1.57-1.82 (m, 2H), 2.02-2.17 (m, 2H), 2.29-2.34 (m,1H), 2.92-3.22 (m, 7H), 3.80 (s, 2H), 4.36-4.42 (m, 1H), 4.37 (s, 2H),4.56 (s, 2H), 7.44 (s, 4H), 7.75 (t, 1H, J=7.0 Hz), 7.80-7.89 (m, 2H),8.24 (d, 1H, J=8.0 Hz), 8.32 (td, 1H, J=8.0, 1.5 Hz), 8.48 (d, 1H, J=5.0Hz), 8.72 (d, 1H, J=5.5 Hz); ¹³C NMR (D₂O) mixture of diastereomers δ9.27, 15.06, 15.28, 19.79, 20.49, 25.77, 26.00, 27.73, 43.17, 43.28,48.42, 48.67, 51.36, 54.62, 56.20, 56.30, 59.51, 59.64, 125.59, 126.99,130.10, 130.82, 130.90, 139.17, 139.73, 140.46, 144.30, 146.22, 147.32,147.55, 151.92. ES-MS m/z 458 (M+H). Anal. Calcd. forC₂₉H₃₉N₅.4.4HBr.3.8H₂O: C, 39.49; H, 5.83; N, 7.94. Found: C, 39.44; H,5.82; N, 7.87.

Example 49 AMD8827: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(2-pyridinylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0300] To a stirred solution of 2-pyridinecarboxaldehyde (1.60 mL, 16.6mmol) in dry MeOH (10 mL) was added ethanolamine (1.0 mL, 16.6 mmol) andthe mixture was stirred for 2 days. The solution was concentrated invacuo and redissolved in dry MeOH (10 mL). To this solution was addedpalladium on activated carbon (10%, 250 mg) and the mixture was stirredfor 20 hours under an atmosphere of hydrogen. The reaction mixture wasfiltered through MgSO₄, concentrated in vacuo, dissolved in THF (20 mL)and protected with di-t-butyldicarbonate (3.55 g, 16.3 mmol) for 2hours. Purification of the crude material by column chromatography onsilica gel (CH₂Cl₂/MeOH, 96:4) gave the desired alcohol as a clear oil:¹H NMR (CDCl₃) δ 1.22 (br s) and 1.40 (br s) (total 9H), 3.58-3.62 (brm, 2H), 3.81-3.83 (br m, 2H), 4.44 (s, 2H), 6.82-6.84 (br m) and7.20-7.25 (m) and 7.33 (d, J=9.0 Hz) and 7.68 (t, J=7.5 Hz) and 8.50 (m,1H) (total 4H).

[0301] Using general procedure F: A solution of the alcohol (330 mg,1.31 mmol) in CH₂Cl₂ (5 mL) was oxidized with Dess-Martin periodinane(670 mg, 1.58 mmol) for 45 min to give the crude aldehyde, which wasused without further purification in the next step.

[0302] Using general procedure A: To a solution ofN-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(250 mg, 0.46 mmol) and the crude aldehyde in MeOH (10 mL) was addedsodium cyanoborohydride (71 mg, 1.13 mmol) and the mixture was stirredfor 16 hours. After work-up, the crude intermediate was purified bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 96:4 to 9:1) to givethe desired intermediate as a yellow oil.

[0303] Using general procedures C and D: The oil from above was reactedwith thiophenol (92 μL, 0.90 mmol) and potassium carbonate (130 mg, 0.94mmol) in CH₃CN (5 mL) for 16 hours. Purification of the crude materialby column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 95:5:0followed by 93:6:1) gave the BOC protected intermediate (47 mg, 17% over2 steps) as a colorless oil. Conversion to the hydrobromide salt withsimultaneous deprotection of the BOC group, followed by re-precipitaionof the crude material from methanol/ether gave AMD8827 (62 mg, 84%) as apale orange solid. ¹H NMR (D₂O) δ 1.71-1.77 (br m, 1H), 2.05-2.17 (br m,2H), 2.27-2.32 (m, 1H), 2.92 (br d, 2H, J=4.8 Hz), 3.00-3.05 (m, 1H),3.15-3.19 (m, 1H), 3.30-3.40 (m, 2H), 3.75 (s, 2H), 4.31 (s, 2H),4.33-4.38 (m, 1H), 4.42 (s, 2H), 4.52 (s, 2H), 7.39 (d, 2H, J=8.0 Hz),7.43 (d, 2H, J=8.0 Hz), 7.67-7.75 (m, 3H), 7.78-7.88 (m, 2H), 8.18 (td,1H, J=7.0, 2.0 Hz), 8.22 (d, 1H, J=7.0 Hz), 8.33 (td, 1H, J=7.0, 2.0Hz), 8.45 (d, 1H, J=6.0 Hz), 8.59 (d, 1H, J=5.0 Hz), 8.70 (d, 1H, J=4.0Hz); ¹³C NMR (D₂O) δ 19.70, 20.50, 27.75, 46.21, 48.19, 48.75, 49.76,51.33, 54.52, 59.25, 125.59, 126.07, 126.30, 126.88 (2 carbons), 130.08,130.88 (4 carbons), 139.20, 139.52, 140.48, 142.52, 144.01, 146.41,147.37 (2 carbons), 147.59, 148.12, 151.82. ES-MS n/z 493 (M+H). Anal.Calcd. for C₃₁H₃₆N₆.4.9HBr.3.3H₂O: C, 39.25; H, 5.05; N, 8.86; Br,41.28. Found: C, 39.20; H, 4.95; N, 8.67; Br, 41.33.

Example 50 AMD8828: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(2-furanylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0304] To a stirred solution of 2-furanaldehyde (4.0 mL, 48.3 mmol) indry MeOH (10 mL) was added ethanolamine (1.5 mL, 24.6 mmol) and themixture stirred for 2 days. The solution was concentrated in vacuo andredissolved in dry MeOH (10 mL). To this solution was added sodiumborohydride (0.50 g, 13.2 mmol) in three portions and the mixturestirred for 40 min. The reaction mixture was concentrated in vacuo andpartitioned between EtOAc (40 mL) and saturated aqueous sodiumbicarbonate (40 mL). The aqueous layer was washed with EtOAc (2×30 mL)and the combined organic phases dried (MgSO₄), filtered and concentratedin vacuo. The crude amine was dissolved in THF (30 mL) and protectedwith di-t-butyldicarbonate (1.95 g, 8.94 mmol) for 3 hours. Afterwork-up, the crude intermediate was purified by column chromatography onsilica gel (hexanes/EtOAc, 3:1 followed by 1:1) to give the desiredalcohol as a clear oil: ¹H NMR (CDCl₃) δ 1.47 (s, 9H), 2.99 (br s, 1H),3.45 (br s, 2H), 3.69-3.71 (br m, 2H), 4.41 (br s, 2H), 6.20 (br s) and6.32 (br s) and 7.35 (s) and 7.40 (s) (total 3H).

[0305] Using general procedure F: A solution of the alcohol (280 mg,1.16 mmol) in CH₂Cl₂ (5 mL) was oxidized with Dess-Martin periodinane(650 mg, 1.53 mmol) for 30 min and the crude aldehyde used withoutfurther purification.

[0306] To a solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(270 mg, 0.50 mmol) and the crude aldehyde in MeOH (5 mL) was addedsodium cyanoborohydride (61 mg, 0.97 mmol) and the mixture was stirredfor 17 hours. Following work-up, the crude material was purified bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 96:4) to give thedesired intermediate as an orange oil.

[0307] The oil from above was dissolved in CH₂Cl₂ (2 mL) and treatedwith trifluoroacetic acid (1 mL) and the mixture was stirred for 30 min.The reaction was concentrated in vacuo then diluted with CH₂Cl₂ (25 mL)and saturated aqueous sodium bicarbonate (25 mL). The organic phase waswashed with saturated aqueous sodium bicarbonate (2×25 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. Purification of the crudeproduct by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,94:5:1) gave the 2-nitrobenzenesulfonyl-protected intermediate (93 mg,28% over 2 steps) as a yellow oil.

[0308] Using general procedures C and D: the oil was reacted withthiophenol (80 μL, 0.78 mmol) and potassium carbonate (140 mg, 1.01mmol) in CH₃CN (5 mL) for 3 hours. Purification of the crude material byby column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 95:5:0followed by 95:4:1) gave the free base of the title compound (24 mg,36%). Conversion of the free base (20 mg, 0.04 mmol) to the hydrobromidesalt followed by re-precipitation of the crude material frommethanol/ether gave AMD8828 (31 mg, 89%) as an off-white solid. ¹H NMR(D₂O) δ 1.71-1.81 (br m, 1H), 2.00-2.16 (br m, 2H), 2.28-2.30 (m, 1H),2.92-2.94 (m, 3H), 3.11-3.26 (m, 3H), 3.72 (s, 2H), 4.15 (s, 2H),4.32-4.46 (m, 1H), 4.34 (s, 2H), 4.53 (s, 2H), 6.44 (s, 1H), 6.52 (s,1H), 7.40 (s, 4H), 7.53 (s, 1H), 7.76 (t, 1H, J=7.0 Hz), 7.78-7.86 (m,2H), 8.24 (d, 1H, J=7.0 Hz), 8.31 (t, 1H, J=8.0 Hz), 8.47 (d, 1H, J=6.0Hz), 8.72 (d, 1H, J=6.0 Hz); ¹³C NMR (D₂O) δ 19.73, 20.50, 27.77, 43.34,45.18, 48.13, 48.67, 51.37, 54.56, 59.45, 111.53, 113.41, 125.64,126.95, 126.98, 130.10, 130.82 (2 carbons), 130.93 (2 carbons), 139.17,139.65, 140.52, 144.25, 144.50, 145.29, 146.28, 147.36, 147.64, 151.82.ES-MS m/z 482 (M+H). Anal. Calcd. for C₃₀H₃₅N₅O.4.1HBr.2.0H₂O: C, 42.42;H, 5.11; N, 8.24; Br, 38.57. Found: C, 42.32; H, 4.93; N, 7.97; Br,38.76

Example 51 AMD8772: Preparation ofN-(2-pyridinylmethyl)-N′-(2-guanidinoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0309]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(2-aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(trifluoroacetic acid salt).

[0310] To a solution of N-Boc-3-aminopropane-1,2-diol (191 mg, 1.0 mmol)in water (10 mL) was added sodium periodate (255 mg, 1.2 mmol). Themixture was then stirred rapidly for 2 hours. Work-up viadichloromethane extraction gave the crude aldehyde, which was useddirectly in the next step without further purification.

[0311] The aldehyde from above,N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(270 mg, 0.5 mmol) and sodium cyanoborohydride (63 mg, 1.0 mmol) werereacted in methanol (10 mL) using general procedure A. Purification ofthe crude intermediate by column chromatography on silica gel (5% MeOHin CH₂Cl₂) gave the desired intermediate (248 mg, 72%). This materialwas then treated with trifluoroacetic acid (1 mL) in CH₂Cl₂ (2 mL) for 1hour. Evaporation of the solvent afforded the title compound inquantitative yield as the TFA salt.

[0312] Preparation of AMD8772.

[0313] To a solution of the TFA salt in THF (20 mL) were addedtriethylamine (0.14 mL, 1.0 mmol) and potassium carbonate (138 mg, 1.0mmol). After stirring at room temperature for 20 minutes,N,N′-di-Boc-pyrazolecarboxamidine (155 mg, 0.5 mmol) was added and themixture was stirred at room temperature for 48 hours. The reaction wasthen treated with saturated aqueous ammonium chloride and extracted withdichloromethane. The combined organic fractions were dried andconcentrated and the residue was purified by column chromatography onsilica gel (5% MeOH in CH₂Cl₂) to afford the desired guanidine (73 mg,25%).

[0314] Using general procedures C and D: the guanidine was reacted withthiophenol (0.045 mL, 0.440 mmol) and potassium carbonate (73 mg, 0.529mmol) in acetonitrile (5 mL). The crude material was purified by columnchromatography on silica gel (10% MeOH in CH₂Cl₂) to give the free baseof the title compound (28 mg, 50%). Conversion to the hydrobromide saltgave AMD8772 (18 mg). ¹H NMR (D₂O) δ 1.75 (m, 1H), 2.00-2.10 (m, 2H),2.30 (m, 2H), 2.91 (m, 2H), 3.10 (m, 1H), 3.36 (m, 2H), 3.86 (d, 1H,J=13.5 Hz), 3.92 (d, 1H, J=13.5 Hz), 4.35 (s, 2H), 4.40 (m, 1H), 4.44(s, 2H), 7.45 (d, 2H, J=7.8 Hz), 7.48 (d, 2H, J=7.8 Hz), 7.59 (m, 1H),7.61 (dd, 1H, J=7.5, 5.7 Hz), 7.71 (m, 1H), 8.07 (d, 1H, J=7.8 Hz), 8.17(t, 1H, J=7.8 Hz), 8.49 (d, 1H, J=5.7 Hz), 8.65 (d, 1H, J=4.8 Hz); ¹³CNMR (D₂O) δ 20.14, 20.44, 27.54, 36.85, 39.06, 49.29, 49.82, 51.20,54.77, 59.91, 125.33, 126.28, 130.67, 130.92, 137.80, 139.12, 141.20,142.73, 145.39, 147.25, 148.25, 151.29, 162.11. ES-MS m/z 444 (M+H).Anal. Calcd. for C₂₆H₃₃N₇.4.3 HBr.2.7 H₂O: C, 37.17; H, 5.12; N, 11.67;Br, 40.90. Found: C, 37.39; H, 3.29; N, 11.53; Br, 40.62.

Example 52 AMD8861: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[bis-[(2-methoxy)phenylmethyl]amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0315] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(2-aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(see prep. of AMD8772) (253 mg, 0.43 mmol) in CH₂Cl₂ (6 mL) was addedo-anisaldehyde (72 mg, 0.53 mmol) and sodium triacetoxyborohydride (174mg, 0.82 mmol) and the mixture was stirred for 6 hours. The reaction wasdiluted with CH₂Cl₂ (25 mL) and saturated sodium bicarbonate (25 mL) andthe aqueous layer washed with CH₂Cl₂ (2×20 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the crude material by column chromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH, 96:4:0 followed by 95:4:1) gave thebis-anisaldehyde reductive amination product (77 mg, 25%) as a clearoil.

[0316] Using general procedures C and D: the intermediate from above (77mg, 0.09 mmol) was reacted with thiophenol (95 mL, 0.91 mmol) andpotassium carbonate (95 mg, 0.69 mmol) in CH₃CN (5 mL) for 16 hours.Purification of the crude material by column chromatography on silicagel (CH₂Cl₂/MeOH/NH₄OH, 96:4:0 followed by 95:4:1) gave the free base ofthe title compound (45 mg, 75%) as a clear oil. Conversion of the freebase (18 mg, 0.028 mmol) to the hydrobromide salt followed byre-precipitaion of the crude material from methanol/ether gave AMD8861(70 mg, 91%) as a white solid. ¹H NMR (D₂O) δ 1.63-1.73 (br m, 2H),2.04-2.12 (br m, 2H), 2.45-2.53 (br m, 1H), 2.81-2.87 (br m, 3H),3.07-3.17 (m, 1H), 3.31-3.37 (m, 1H), 3.57 (d, 1H, J=13.0 Hz), 3.64 (d,1H, J=13.0 Hz), 3.79 (s, 3H), 3.84 (s, 3H), 3.96-4.01 (m, 1H), 4.19 (d,1H, J=13.2 Hz), 4.26 (d, 1H, J=13.5 Hz), 4.32 (s, 2H), 4.42 (s, 2H),4.45 (s, 2H), 6.87-7.00 (m, 3H), 7.07 (d, 1H, J=7.0 Hz), 7.21 (d, 2H,J=7.0 Hz), 7.33-7.37 (m, 1H), 7.36 (br s, 4H), 7.46 (t, 1H, J=8.0 Hz),7.64-7.67 (m, 1H), 7.67 (d, 1H, J=8.0 Hz), 7.78 (t, 1H, J=7.0 Hz), 8.13(t, 1H, J=8.0 Hz), 8.25 (d, 1H, J=8.0 Hz), 8.38 (d, 1H, J=5.0 Hz), 8.63(d, 1H, J=5.0 Hz); ¹³C NMR (D₂O) δ 20.24, 20.27, 27.56, 46.02, 49.23,51.19, 51.42, 54.73, 56.23 (3 carbons), 56.29, 58.69, 111.65, 111.87,117.61, 117.76, 121.82, 121.88, 125.84, 126.13, 126.24, 130.14, 130.40(2 carbons), 130.79 (2 carbons), 132.21, 132.32, 132.68 (2 carbons),139.28, 139.38, 140.35, 142.52, 147.35, 147.73, 148.32, 151.64, 157.94,158.10. ES-MS m/z 642 (M+H). Anal. Calcd. for C₄₁H₄₇N₅O₂.4.2HBr.3.1H₂O:C, 47.46; H, 5.58; N, 6.75; Br, 32.35. Found: C, 47.51; H, 5.61; N,6.66; Br, 32.36.

Example 53 AMD8862: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-4-ylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (hydrobromide salt)

[0317] To a stirred suspension of 4(5)-imidazolecarboxaldehyde (682 mg,7.10 mmol) in dry MeOH (5 mL) was added ethanolamine (0.52 mL, 8.52mmol) and the mixture was stirred for 3.5 hours. To this solution wasadded sodium borohydride (322 mg, 8.52 mmol) in three portions and themixture was stirred for 1 hour. The reaction mixture was concentrated invacuo and diluted with saturated aqueous sodium bicarbonate (40 mL). Tothis solution was added di-tert-butyldicarbonate (3.2 g, 14.0 mmol) andthe mixture stirred for 16 hours, resulting in the formation a whiteprecipitate. The aqueous phase was extracted with EtOAc (2×40 mL) andthe combined organic extracts dried (MgSO₄), filtered and concentratedin vacuo. Purification of the crude material by column chromatography onsilica gel (CH₂Cl₂/MeOH, 96:4) gave the desired Boc-protected imidazolealcohol as a clear oil. ¹H NMR (CDCl₃) δ 1.36 (br s, 18H), 3.39 (br s,2H), 3.65-3.70 (br s, 2H), 4.24 (s, 2H), 5.84 (br s) and 6.30 (br s)(total 1H), 7.15 (s) and 7.23 (s) (total 1H), 7.96 (s, 1H).

[0318] Using general procedure F: A solution of the alcohol from above(568 mg, 1.67 mmol) in CH₂Cl₂ (10 mL) was oxidized with Dess-Martinperiodinane (1.44 g, 3.40 mmol) for 1 hour and the crude aldehyde wasused without further purification in the next step.

[0319] Using general procedure B: To a solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(368 mg, 0.68 mmol) and the crude aldehyde from above in CH₂Cl₂ (10 mL)was added sodium triacetoxyborohydride (204 mg, 0.96 mmol) and themixture was stirred for 17 hours. Purification of the crude product bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 96:4 to 92:8) gave thedesired tertiary amine (277 mg, 47%) as a clear oil.

[0320] Using general procedures C and D: the oil (277 mg, 0.32 mmol) wasreacted with thiophenol (0.17 mL, 1.6 mmol) and potassium carbonate (265mg, 1.92 mmol) in CH₃CN (5 mL) for 1.5 hours. Purification of the crudematerial by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,96:4:0 followed by 95:4:1) gave the corresponding amine (123 mg, 57%) asa clear oil. Conversion of the free amine (87 mg, 0.13 mmol) to thecorresponding hydrobromide salt with simultaneous deprotection of theBoc groups, followed by re-precipitation of the crude material frommethanol/ether gave AMD8862 (105 mg, 87%) as a beige solid. ¹H NMR (D₂O)δ 1.71-1.76 (br m, 1H), 2.03-2.14 (br m, 2H), 2.29-2.31 (br m, 1H), 2.91(br d, 2H, J=4.8 Hz), 2.98-3.05 (m, 1H), 3.14-3.20 (m, 1H), 3.30-3.41(m, 2H), 3.77 (s, 2H), 4.35 (s, 2H), 4.35-4.40 (m, 1H), 4.41 (s, 2H),4.56 (s, 2H), 7.40 (d, 2H, J=8.0 Hz), 7.44 (d, 2H, J=8.0 Hz), 7.69 (s,1H), 7.72 (d, 1H, J=7.0 Hz), 7.86 (t, 1H, J=7.0 Hz), 7.92 (d, 1H, J=8.0Hz), 8.20 (d, 1H, J=8.0 Hz), 8.37 (t, 1H, J=8.0 Hz), 8.44 (d, 1H, J=6.0Hz), 8.74 (d, 1H, J=5.0 Hz), 8.79 (s, 1H); ¹³C NMR (D₂O) δ 19.77, 20.52,27.71, 40.68, 46.07,48.39, 48.61, 51.48, 54.54, 59.33, 121.64, 123.20,125.56, 127.27, 127.42, 130.00, 130.88 (4 carbons), 135.80, 139.13,139.51, 140.37, 145.11, 145.71, 146.86, 147.60, 151.83. ES-MS m/z 482(M+H). Anal. Calcd. for C₂₉H₃₅N₇.5.1HBr.2.9H₂O: C, 36.80; H, 4.89; N,10.36; Br, 43.05. Found: C, 36.93; H, 4.66; N, 10.28; Br, 42.83.

Example 54 AMD8887: Preparation ofN-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-ylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0321] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(2-aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(333 mg, 0.57 mmol) in dry MeOH (5 mL) was added2-imidazolecarboxaldehyde (110 mg, 1.14 mmol) and the mixture wasstirred for 17 hours. To this solution was added sodium borohydride (110mg, 2.91 mmol) in one portion and the mixture was stirred for 40 min.The reaction mixture was concentrated in vacuo and partitioned betweenCH₂Cl₂ (25 mL) and saturated aqueous sodium bicarbonate (25 mL). Theaqueous layer was washed with CH₂Cl₂ (2×20 mL) and the combined organicphases were dried (Na₂SO₄), filtered and concentrated in vacuo. Thecrude amine was dissolved in THF (10 mL) and protected withdi-t-butyldicarbonate (1.0 g, 4.59 mmol). Purification of the crudematerial by column chromatography on silica gel (CH₂Cl₂/MeOH, 96:4followed by 9:1) gave the desired product (110 mg, 22%) as a yellow oil.

[0322] Using general procedures C and D: to a solution of theintermediate from above (110 mg, 0.14 mmol) in CH₃CN (5 mL) was addedthiophenol (72 μL, 0.70 mmol) and potassium carbonate (116 mg, 0.84mmol). The reaction was stirred for 20 hours. The crude material waspurified by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,95:5:0 followed by 95:4:1) to give the amine (54 mg, 65%) as an orangeoil. Conversion of the free base (25 mg, 0.04 mmol) to a hydrobromidesalt gave AMD8887 (30 mg, 67%) as a white solid. ¹H NMR (D₂O) δ1.73-1.80 (br m, 1H), 2.02-2.14 (br m, 2H), 2.27-2.31 (br m, 1H), 2.90(br d, 2H, J=5.1 Hz), 2.99-3.03 (m, 1H), 3.06-3.23 (m, 1H), 3.33-3.48(m, 2H), 3.77 (d, 1H, J=13.2 Hz), 3.84 (d, 1H, J=13.5 Hz), 4.33 (s, 2H),4.33-4.37 (m, 1H), 4.54 (s, 2H), 4.67 (s, 2H), 7.38 (d, 2H, J=8.1 Hz),7.43 (d, 2H, J=8.1 Hz), 7.56 (s, 2H), 7.70 (dd, 1H, J=7.5, 6.3 Hz), 7.80(dd, 1H, J=7.5, 6.6 Hz), 7.84 (d, 1H, J=8.1 Hz), 8.18 (d, 1H, J=8.1 Hz),8.29 (t, 1H, J=8.1 Hz), 8.43 (d, 1H, J=5.7 Hz), 8.71 (d, 1H, J=5.1 Hz);¹³C NMR (D₂O) δ 19.83, 20.50, 27.68, 40.59, 46.71, 48.73 (2 carbons),51.38, 54.53, 59.41, 121.56 (2 carbons), 125.54, 126.94, 126.99, 130.10,130.86 (4 carbons), 135.91, 139.21, 139.27, 140.28, 144.24, 146.29,147.37, 147.50, 151.75. ES-MS m/z 482 (M+H). Anal. Calcd. forC₂₉H₃₅N₇.5.1HBr.3.0H₂O: C, 36.73; H, 4.90; N, 10.34; Br, 42.97. Found:C, 36.97; H, 4.57; N, 9.98, Br, 42.78.

Example 55 AMD8816: Preparation ofN-(2-pyridinylmethyl)-N′-[2-(phenylureido)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0323] Reaction of Boc-aminoacetaldehyde (1.0 mmol) withN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(270 mg, 0.5 mmol) in the presence of sodium cyanoborohydride inmethanol affordedN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-[2-[(t-butyloxycarbonyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(248 mg, 72%). This material was then treated with trifluoroacetic acid(1 mL) in CH₂Cl₂ (2 mL) for 1 hour. Evaporation of the solvent affordedthe primary amine in quantitative yield as the TFA salt.

[0324] The amine TFA salt was then treated with aqueous sodium hydroxide(1.0 M) and extracted into dichloromethane. The free base was then driedand concentrated, taken up into dichloromethane and reacted withphenylisocyanate (0.048 mL, 0.42 mmol). Following work-up andpurification by column chromatography, the desired urea was obtained (64mg, 23%).

[0325] Using general procedures C and D: reaction of the urea withthiophenol gave the corresponding amine (41 mg, 87%) which was convertedto a hydrobromide salt giving AMD8816 (38 mg). ¹H NMR (D₂O) δ: 1.77 (m,1H), 2.10 (m, 2H), 2.48 (m, 1H), 2.85 (m, 2H), 3.15-1.33 (m, 4H), 4.17(br s, 2H), 4.39 (s, 2H), 4.56 (s, 2H), 7.11 (d, 1H, J=6.7 Hz), 7.32 (m,4H), 7.46 (m, 2H), 7.68 (m, 5H), 8.13 (dd, 1H, J=8.1, 5.8 Hz), 8.41 (brs, 1H), 8.62 (d, 1H, J=5.8 Hz), 8.81 (d, 1H, J=5.3 Hz); ¹³C NMR (D₂O) δ20.33, 20.70, 27.35, 36.14, 49.10, 50.88, 54.54, 61.69, 66.46, 120.93,124.38, 124.86, 126.38, 129.76, 131.33, 131.40, 132.01, 133.00, 136.43,138.40, 142.88, 146.31, 147.11, 147.98, 148.96, 161.32. ES-MS m/z 521(M+H). Anal. Calcd. for C₃₂H₃₆N₆O.4.1 HBr.1.7H₂O: C, 44.55; H, 4.95; N,8.80; Br, 34.32. Found: C, 44.56; H, 5.04; N, 8.86; Br, 34.28.

Example 56 AMD8737: Preparation ofN-(2-pyridinylmethyl)-N′-[[N″-(n-butyl)carboxamido]methyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1.4-benzenedimethanamine(hydrobromide salt)

[0326] 2-bromo-N-(n-butyl)-acetamide.

[0327] To a solution of n-butyl amine (0.62 mL, 6.3 mmol) and Et₃N (2mL, 14 mmol) in CH₂Cl₂ (10 mL), cooled to 0° C., was added dropwise asolution of bromoacetyl bromide (0.5 mL, 5.7 mmol) in CH₂Cl₂ (5 mL). Thereaction mixture was warmed to room temperature and stirred for 30 min.The mixture was then diluted with CH₂Cl₂ (15 ml) and washed with aqueous1 N HCl (15 mL), saturated aqueous sodium bicarbonate (15 mL) and brine(15 mL). The organic phase was dried (MgSO₄), filtered and concentratedin vacuo to give the crude product as a dark oil. ¹H NMR (CDCl₃) δ 0.94(t, 3H, J=6.0 Hz), 1.33-1.56 (m, 4H), 3.32 (q, 2H, J=6.0 Hz), 3.89 (s,2H), 6.49 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.58, 19.86, 29.24, 31.15,39.82, 165.40. This was used without further purification in the nextstep.

[0328] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(188 mg, 0.35 mmol) in dry CH₃CN (5 mL) was added a solution of2-bromo-N-(n-butyl)-acetamide (170 mg, 0.88 mmol) in CH₃CN (2 mL) andpowdered potassium carbonate (295 mg, 2.14 mmol). The mixture wasstirred for 2 days then concentrated in vacuo and partitioned betweenCH₂Cl₂ (30 mL) and water (30 mL). The aqueous layer was washed withCH₂Cl₂ (2×25 mL) and the combined organic phases were dried (MgSO₄),filtered and concentrated in vacuo. Purification of the resultant crudeoil by column chromatography with silica gel (CH₂Cl₂/MeOH, 96:4 followedby 9:1) afforded the desired product (89 mg, 39%) as a colorless oil.

[0329] Using General procedures C and D: the intermediate from above(114 mg, 0.17 mmol) was reacted with thiophenol (89 μL, 0.87 mmol) andpotassium carbonate (144 mg, 1.04 mmol) in CH₃CN (5 mL) for 2 hours. Thecrude product was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 97:3 to 9:1) to give the free base of the title compound(49 mg, 60%) as a pale yellow oil. Conversion of the free base (49 mg,0.10 mmol) to the hydrobromide salt gave AMD8737 (77 mg, 94%) as a paleyellow solid. ¹H NMR (D₂O) δ 0.78 (t, 3H, J=6.6 Hz), 1.11-1.18 (q, 2H,J=6.9 Hz), 1.23-1.29 (m, 2H), 1.68-1.86 (m, 1H), 2.00-2.13 (m, 2H),2.28-2.40 (m, 1H), 2.90-2.95 (m, 4H), 3.41 (d, 2H, J=15.9 Hz), 3.56 (d,2H, J=15.9 Hz), 4.35 (s, 2H), 4.35-4.41 (m, 1H), 4.54 (s, 2H), 7.43 (brs, 4H), 7.68 (t, 1H, J=5.7 Hz), 7.78-7.86 (m, 2H), 8.13 (d, 1H, J=7.8Hz), 8.30 (t, 1H, J=7.7 Hz), 8.50 (d, 1H, J=5.4 Hz), 8.71 (d, 1H, J=5.1Hz); ¹³C NMR (D₂O) δ 13.35, 19.80, 20.46, 20.97, 27.52, 30.72, 39.52,48.62, 51.40, 55.51, 55.93, 61.56, 125.46, 126.96, 126.98, 130.36,130.72 (2 carbons), 131.14 (2 carbons), 138.06, 139.60, 140.36, 144.32,146.08, 146.17, 147.31, 151.25, 172.15. ES-MS m/z 472 (M+H). Anal.Calcd. for C₂₉H₃₇N₅O.4.0HBr.1.3H₂O.1.3CH₃CO₂H: C, 42.32; H, 5.48; N,7.81; Br, 35.64. Found: C, 42.38; H, 5.47; N, 7.84; Br, 35.66.

Example 57 AMD8739: Preparation ofN-(2-pyridinylmethyl)-N′-(carboxamidomethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0330] A solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(151 mg, 0.28 mmol) in CH₃CN (5 mL) was treated with 2-bromoacetamide(154 mg, 1.12 mmol) and potassium carbonate (190 mg, 1.38 mmol) for 19hours. After work-up the crude product was used without furtherpurification.

[0331] Using general procedures C and D: the intermediate from above wasreacted with thiophenol (0.15 mL, 1.46 mmol) and potassium carbonate(242 mg, 1.75 mmol) in CH₃CN (5 mL) for 1.5 hours. The crude materialwas purified by column chromatography on silica gel (CH₂Cl₂/MeOH, 95:5to 9:1) to afford the free base of the title compound (32 mg, 28% for 2steps) as a colorless oil. Conversion of the free base (32 mg, 0.06mmol) to the hydrobromide salt gave AMD8739 (35 mg, 68%). ¹H NMR (D₂O) δ1.73-1.79 (m, 1H), 1.93-2.14 (m, 2H), 2.89 (m, 2H), 3.45 (d, 1H, J=16.2Hz), 3.62 (d, 1H, J=16.2 Hz), 3.91 (s, 2H), 4.38 (s, 3H), 4.37-4.43 (m,1H), 4.63 (s, 2H), 7.41 (d, 2H, J=7.5 Hz), 7.47 (d, 2H, J=7.5 Hz), 7.66(t, 1H, J=6.9 Hz), 7.95 (t, 1H, J=6.9 Hz), 8.02 (d, 1H, J=7.8 Hz), 8.11(d, 1H, J=7.5 Hz), 8.44-8.49 (m, 2H), 8.77 (d, 1H, J=4.9 Hz); ¹³C NMR(D₂O) δ 20.46, 20.90, 27.51, 47.80, 51.64, 54.63, 55.45, 60.88, 125.43,127.74, 128.02, 130.27, 130.79 (2 carbons), 131.15 (2 carbons), 138.07,139.52, 140.43, 144.77, 146.05 (2 carbons), 146.43, 151.30, 175.37.ES-MS m/z 416 (M+H). Anal. Calcd. forC₂₅H₂₉N₅O.4.8HBr.2.3H₂O.0.6CH₃CO₂H: C, 35.70; H, 4.67; N, 7.95; Br,43.52. Found: C, 35.74; H, 4.44; N, 8.02; Br, 43.31.

Example 58 AMD8752: Preparation ofN-(2-pyridinylmethyl)-N′-[(N″-phenyl)carboxamidomethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0332] 2-bromoacetanilide (Ronsisvalle, G. et al. J. Med. Chem. 1998,41, 1574-1580).

[0333] To a stirred solution of bromoacetyl chloride (1.36 mL, 16.4mmol) in dry THF (5 mL) cooled to 0° C., was added dropwise a solutionof aniline (1.0 mL, 11.0 mmol) and 4-(dimethylamino)pyridine (0.63 g,5.2 mmol) in dry THF (10 mL). After 1 h the mixture was quenched withwater (25 mL) and extracted with CH₂Cl₂ (2×30 mL). The organic extractswere washed with a saturated aqueous sodium bicarbonate solution (30mL), dried (Na₂SO₄) and concentrated in vacuo to give a white solid. ¹HNMR (CDCl₃) δ 4.03 (s, 2H), 7.20 (td, 1H, J=7.5, 0.9 Hz), 7.36 (td, 2H,J=7.5 Hz, 0.9 Hz), 7.54 (dd, 2H, J=7.5, 0.9 Hz), 8.17 (br m, 1H). Thecrude solid was used without further purification in the next step.

[0334] A solutionN-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(154 mg, 0.34 mmol) in CH₃CN (6 mL) was treated with 2-bromoacetanilide(185 mg, 0.86 mmol) and potassium carbonate (140 mg, 1.0 mmol) and themixture was stirred for 2 days. Purification of the crude material bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 98:2 to 95:5) gave thedesired product (47 mg, 24%) as a white foam.

[0335] Using general procedure D: the intermediate from above (47 mg,0.08 mmol) was converted to the hydrobromide salt with simultaneousdeprotection of the BOC group to give AMD8752 (57 mg, 87%) as a whitesolid. ¹H NMR (D₂O) δ 1.85-1.89 (m, 1H), 2.08-2.15 (m, 2H), 2.42-2.46(m, 1H), 2.97-3.00 (br s, 2H), 3.55 (d, 1H, J=16.2 Hz), 3.73 (d, 1H,J=16.2 Hz), 3.92 (d, 1H, J=12.6 Hz), 4.01 (d, 1H, J=12.6 Hz) 4.30 (br s,4H), 4.58-4.61 (m, 1H), 6.99 (t, 1H, J=6.6 Hz), 7.17-7.25 (m, 4H), 7.43(d, 2H, J=7.5 Hz), 7.55 (d, 2H, J=7.5 Hz), 7.79 (t, 1H, J=6.3 Hz), 7.96(d, 1H, J=8.1 Hz), 8.03 (t, 1H, J=6.6 Hz), 8.25 (d, 1H, J=7.8 Hz), 8.54(t, 1H, J=8.1 Hz), 8.61 (d, 1H, J=5.1 Hz), 8.81 (d, 1H, J=5.1 Hz); ¹³CNMR (D₂O) δ 20.54, 21.29, 27.65, 47.20, 51.45, 56.51, 56.92, 62.56,122.15 (2 carbons), 125.73, 126.06, 127.96, 128.25, 129.43 (2 carbons),129.99, 130.83 (2 carbons), 131.67 (2 carbons), 136.40, 138.48, 140.12(2C), 144.80, 145.84, 146.64, 146.76, 151.20, 171.61. ES-MS m/z 492(M+H). Anal. Calcd. for C₃₁H₃₃N₅O.4.0HBr.2.3H₂O: C, 43.46; H, 4.89; N,8.17; Br, 37.3 1. Found: C, 43.44; H, 4.84; N, 7.99; Br, 37.31.

Example 59 AMD8765: Preparation ofN-(2-pyridinylmethyl)-N′-(carboxymethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0336] To a solution ofN-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(230 mg, 0.50 mmol) and t-butyl bromoacetate (0.15 mL, 1.02 mmol) inCH₃CN (8 mL) was added powdered potassium carbonate (220 mg, 1.60 mmol)and the mixture was stirred for 16 hours. The crude material waspurified by column chromatography on silica gel (CH₂Cl₂/MeOH, 98:2 to95:5) to give the desired product (160 mg, 56%) as a yellow oil.

[0337] Using general procedure D: the oil from above (100 mg, 0.17 mmol)was converted to the hydrobromide salt with simultaneous deprotection ofthe BOC and t-butyl ester groups to give AMD8765 (147 mg, quantitative)as a pale yellow solid. ¹H NMR (D₂O) δ 1.71-1.80 (br m, 1H), 1.92-2.12(br m, 2H), 2.32-2.35 (m, 1H), 2.86-2.88 (m, 2H), 3.51 (d, 1H, J=17.4Hz), 3.67 (d, 1H, J=17.4 Hz), 3.90 (s, 2H), 4.38-4.41 (m, 1H), 4.38 (s,2H), 4.66 (s, 2H), 7.40 (d, 2H, J=8.1 Hz), 7.46 (d, 2H, J=8.1 Hz), 7.66(dd, 1H, J=6.8, 5.7 Hz), 7.67 (d, 1H, J=7.8 Hz), 8.03 (dd, 1H, J=7.2,6.6 Hz), 8.10 (d, 1H, J=7.8 Hz), 8.11 (d, 1H, J=7.2 Hz), 8.48 (d, 1H,J=5.1 Hz), 8.56 (td, 1H, J=7.8, 1.5 Hz), 8.79 (dd, 1H, J=4.8, 0.9 Hz);¹³C NMR (D₂O) δ 20.51, 20.97, 27.43, 47.33, 51.75, 53.29, 55.21, 60.36,125.47, 128.15, 128.55, 130.01, 130.81 (2 carbons), 131.08 (2 carbons),138.47, 139.57, 140.02, 144.04, 145.46, 146.36, 147.49, 151.59, 175.40.ES-MS m/z 417 (M+H). Anal. Calcd. forC₂₅H₂₈N₄O₂.4.1HBr.1.3H₂O.1.2CH₃CO₂H: C, 39.00; H, 4.72; N, 6.64; Br,38.83. Found: C, 39.14; H, 4.62; N, 6.68; Br, 38.54.

Example 60 AMD8715: Preparation ofN-(2-pyridinylmethyl)-N′-(phenylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0338] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.220 g, 0.390 mmol) in CH₃CN (8 mL), at room temperature, was addedpowdered K₂CO₃ (0.153 g, 1.11 mmol) followed by excess benzyl bromide(0.20 mL, 1.68 mmol). After 18 hours, the reaction mixture wasconcentrated and the residue was partitioned between CH₂Cl₂ (10 mL) andwater (5 mL). The phases were separated and the aqueous phase wasextracted with CH₂Cl₂ (2×10 mL). The combined organic extracts weredried (Na₂SO₄) and concentrated. Purification of the crude material byradial chromatography (2 mm plate, 20:1 CH₂Cl₂-CH₃OH) provided thedesired product (0.106 g, 44%) as a white solid.

[0339] To a stirred solution of the intermediate from above (0.106 g,0.173 mmol) in anhydrous CH₃CN (3.5 mL, concentration ˜0.05 M), at roomtemperature, was added neat thiophenol (0.10 mL, 0.974 mmol, ˜5 equiv.)followed by powdered K₂CO₃ (0.140 g, 1.01 mmol, ˜5-10 equiv.). Theresultant bright yellow solution was stirred for at room temperatureovernight. The solvent was removed under reduced pressure and CH₂Cl₂ (10mL) and water (1 mL) were added to the residue. The phases wereseparated and the aqueous phase was extracted with CH₂Cl₂ (3×5 mL). Thecombined organic phases were dried (Na₂SO₄) and concentrated.Purification of the crude material by column chromatography on silicagel (15:1 CH₂Cl₂-MeOH) the free base of the title compound (0.052 g,66%) as a yellow oil.

[0340] To a solution of the free base (0.052 g, 0.115 mmol) in a minimumof 1,4-dioxane (˜0.5 mL) was added HBr saturated dioxane (˜1 mL)dropwise. Ether (15 mL) was added to precipitate a white solid, whichwas allowed to settle to the bottom of the flask and the supernatantsolution was decanted. The solid was washed by decantation with ether(3×15 mL) and the remaining traces of solvent were removed under vacuum.The solid was dried in a vacuum oven (40° C. ® 0.1 Torr) to give AMD8715(0.071 g) as a white powder. ¹H NMR (D₂O) δ 1.64-1.82 (m, 1H), 2.15-2.26(m, 2H), 2.47-2.54 (m, 1H), 2.83 (br s, 2H), 4.29 (s, 2H), 4.33 (s, 2H),4.40 (s, 2H), 4.52-4.59(m, 3H), 7.41-7.54 (m, 10H), 7.76 (d, 1H, J=7.5Hz), 7.84 (t, 1H, J=6.5 Hz), 7.91 (d, 1H, J=7.8 Hz), 8.35 (t, 1H, J=7.5Hz), 8.46 (d, 1H, J=4.5 Hz), 8.74 (d, 1H, J=5.1 Hz); ¹³C NMR (D₂O) δ20.40, 20.56, 27.41, 48.48, 51.37, 54.93, 55.67, 60.99, 124.91, 127.17,127.27, 129.66 (2 carbons), 129.91, 130.50 (2 carbons), 131.13 (2carbons), 131.34 (2 carbons), 131.46, 132.28, 134.21, 136.84, 141.53,144.87, 144.98, 145.84, 146.99, 149.63. ES-MS m/z 449 (M+H). Anal.Calcd. for C₃₀H₃₂N₄.4.0HBr.2.1H₂O.1.4dioxane: C, 45.81; H, 5.55; N,6.00; Br, 34.24. Found: C, 45.68; H, 5.47; N, 6.00; Br, 34.54.

Example 61 AMD8907: Preparation ofN-(2-pyridinylmethyl)-N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0341] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.425 g, 0.78 mmol) in anhydrous DMF (7.5 mL) was addeddi-isopropylethylamine (0.15 mL, 2.80 mmol) followed bychloromethylbenzimidazole (0.129 g, 0.77 mmol). The resultant solutionwas heated to 80° C. for 24 hours then cooled to room temperature. Themixture was concentrated and the residue was partitioned between CH₂Cl₂(40 mL) and brine (10 mL). The phases were separated and the aqueousphase was extracted with CH₂Cl₂ (2×10 mL). The combined organic extractswere dried (Na₂SO₄) and concentrated. The crude material was purified bycolumn chromatography on silica gel (20:1 CH₂Cl₂-CH₃OH containing 1%NH₄OH) followed by radial chromatography on silica gel (2 mm plate, 20:1CH₂Cl₂-CH₃OH containing 1% NH₄OH) to provide the desired tertiary amine(0.169 g, 31%) as a yellow solid.

[0342] Using general procedures C and D: the yellow solid was treatedwith thiophenol (0.15 mL, 1.46 mmol) and K₂CO₃ (0.354 g, 2.56 mmol) inCH₃CN (5 mL). Purification of the crude material by radialchromatography on silica gel (2 mm plate, 50:1:1 CH₂Cl₂-CH₃OH-NH₄OH)provided the free base of the title compound (0.061 g) as a yellow oil.The oil was converted to the hydrobromide salt to give AMD8907 (0.079 g)as a white solid. ¹H NMR (D₂O) δ 1.93-1.98 (m, 1H), 2.19-2.31 (m, 2H),2.41-2.46 (m, 1H), 3.20 (br s, 2H), 3.77-3.88 (m, 4H), 4.16 (s, 2H),4,44 (d, 1H, J=16.5 Hz), 4.63 (d, 1H, J=16.5 Hz), 4.73-4.79 (m, 1H,overlaps with HOD), 7.04 (d, 2H, J=8.1 Hz), 7.23 (d, 2H, J=7.8 Hz), 7.37(dd, 2H, J=3.0, 6.3 Hz), 7.54 (dd, 2H, J=3.0, 6.3 Hz), 7.67 (d, 1H,J=7.8 Hz), 7.72 (dd, 1H, J=6.3, 6.9 Hz), 7.91 (dd, 1H, J=6.0, 7.8 Hz),8.20 (t, 1H, J=7.8 Hz), 8.39 (d, 1H, J=8.1 Hz), 8.67 (d, 1H, J=5.1 Hz),8.75 (d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 20.46, 20.97, 27.87, 48.88,50.22, 50.44, 56.71, 63.26, 113.92, 126.15, 126.43, 126.52, 126.65,130.04, 130.22, 130.47, 130.92, 138.23, 139.70, 141.05, 142.99, 147.15,147.95, 148.32, 150.80, 151.79. ES-MS m/z 489 (M+H). Anal. Calcd. forC₃₁H₃₂N₆.4.0HBr.2.0H₂O: C, 43.89 H, 4.75; N, 9.91; Br, 37.68. Found: C,44.08; H, 4.79; N, 9.71; Br, 37.53.

Example 62 AMD8927: Preparation ofN-(2-pyridinylmethyl)-N′-(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0343] To a stirred solution of 4,5-dimethylphenylene-1,2-diamine (680mg, 5 mmol) in 4N HCl (12 mL) was added chloroacetic acid (940 mg, 10mmol). The solution was then heated to reflux for 17 hours, then cooledto room temperature. Solid sodium carbonate was then added slowly, withstirring, until the pH of the solution was approximately 9.0, at whichpoint a beige precipitate formed. The aqueous phase was then dilutedwith water (10 mL) and extracted repeatedly with ethyl acetate. Thecombined organic fractions were then dried, concentrated and the residuewas purified by column chromatography on silica gel (10% MeOH in CH₂Cl₂)to afford the desired 2-(chloromethyl)-5,6-dimethylbenzimidazole (530mg, 54%). ¹H NMR (CDCl₃) δ 1.59 (br s, 1H), 2.31 (s, 6H), 4.83 (s, 2H),7.42 (s, 2H).

[0344] In a similar manner to the procedure described above: Reaction of2-(chloromethyl)-5,6-dimethylbenzimidazole (195 mg, 1.0 mmol),N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(543 mg, 1.0 mmol) and diisopropylethylamine (0.26 mL, 1.5 mmol) in DMF(8 mL) afforded, following work-up and purification of the crudematerial by column chromatography on silica gel (10% MeOH in CH₂Cl₂),the desired 5,6-dimethylbenzimidazole derivative (280 mg, 38%).

[0345] Using general procedures C and D: the intermediate from above wasreacted with thiophenol (0.230 mL, 2.25 mmol) and potassium carbonate(414 mg, 3.00 mmol) in acetonitrile (8 mL). The crude material waspurified by column chromatography on silica gel (85% CH₂Cl₂, 10% MeOHand 5% NH₄OH) to give the free base of the title compound (181 mg).Conversion of the free base to a hydrobromide salt gave AMD8927 as apale yellow solid (205 mg). ¹H NMR (D₂O) δ 1.89 (br m, 1H), 2.21 (s,6H), 2.27-2.41 (m, 4H), 3.03 (br s, 2H), 3.52 (dd, 1H, J=14.9, 7.2 Hz),3.76 (s, 2H), 3.80 (m, 2H), 4.06 (s, 2H), 4.40 (d, 1H, J=16.5 Hz), 4.56(d, 1H, J=16.5 Hz), 7.04 (d, 2H, J=7.5 Hz), 7.31 (d, 2H, J=7.5 Hz), 7.30(s, 2H), 7.61 (d, 1H, J=7.8 Hz), 7.72 (t, 1H, J=6.5 Hz), 7.93 (t, 1H,J=6.8 Hz), 8.19 (t, 1H, J=7.8 Hz), 8.40 (d, 1H, J=7.8 Hz), 8.68 (d, 1H,J=4.8 Hz), 8.76 (d, 1H, J=5.1 Hz). ¹³C NMR (D₂O) δ 14.52, 19.81, 40.44,20.94, 27.85, 46.66, 50.14, 56.76, 63.31, 66.46, 113.43, 126.12, 126.49,129.00, 129.71, 130.11, 130.58, 130.86, 136.74, 138.23, 139.68, 141.03,142.83, 147.42, 147.93, 148.29, 150.33, 150.81. ES-MS m/z 517 (M+H).Anal. Calcd. for C₃₃H₃₆N₆.4.1HBr.1.6H₂O.1.1HOAc: C, 44.82 H, 5.10; N,8.91; Br, 34.73. Found: C, 44.67; H, 5.08; N, 8.88; Br, 34.89.

Example 63 AMD8926: Preparation ofN-(2-pyridinylmethyl)-N′-(5-nitro-1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine

[0346] N-Dimethylsulfamyl-(nitro)-benzimidazole

[0347] To a pre-cooled (ice bath) solution of 5-nitro-benzimidazole (744mg, 4.56 mmol) and triethylamine (1 mL, 6.93 mmol) in anhydrous CH₂Cl₂(20 mL) was added N,N-dimethyl sulfamoylchloride (0.59 mL, 5.49 mmol)under N₂ and ice bath was removed after addition. Stirring was continuedfor 18 hours under reflux, then reaction mixture was cooled andconcentrated. The residue was diluted with ethylacetate (300 mL), andorganic phase was washed with 1N NaOH solution, sat. NaHCO₃, then brineand dried over Na₂SO₄. Evaporation of the solvent and purification ofthe residue by column chromatography on silica gel (2.5×20 cm, 2:8EtOAc/CH₂Cl₂) gave the desired products as mixture of two regioisomers(720 mg, 60%) as a yellow solid.

[0348] N-Dimethylsulfamyl-2-hydroxymethyl-(nitro)-benzimidazole

[0349] To pre-cooled suspended mixture of1-dimethylsulfamyl-nitro-benzimidazole (mixture of two regioisomers, 421mg, 1.56 mmol) in THF (2 mL) at −78° C. was added LDA (0.4 M, 6.0 mL,2.4 mmol). The resulting mixture was allow to stir for 30 min at −78°C., paraformaldehyde (500 mg, excess) in THF (2 mL) was added. Stirringwas continued for 18 hours at room temperature. The mixture was dilutedwith ethylacetate (300 mL), and washed with sat. NaHCO₃, and brine thendried over Na₂SO₄. Evaporation of the solvent and purification of thecrude material by column chromatography on silica gel (2.5×20 cm, 3:7EtOAc/hexanes) gave the desired product as a yellow solid (mixture oftwo regioisomers) (80 mg, 17%).

[0350] To a pre-cooled (ice bath) solution of1-dimethylsulfamyl-2-hydroxymethyl-(nitro)-benzimidazole (240 mg, 0.80mmol) and triethylamine (0.9 ml, 6.23 mmol) in anhydrous CH₂Cl₂ (6 ml)was added methanesulfonyl chloride (1 N in CH₂Cl₂, 0.8 mL, 0.80 mmol).Stirring was continued for 1 hour at 0° C. The reaction mixture wasdiluted with ethylacetate (300 mL), and washed with sat. NaHCO₃, thenbrine and dried over Na₂SO₄. Evaporation of the solvent and purificationof the residue by column chromatography on silica gel (1.5×20 cm, 2:8EtOAc/hexanes) gave the desired product (240 mg, 83%) as a yellow solid.

[0351] To a stirred solution of1-dimethylsulfamyl-2-methanesulfonylmethyl-[4(5)-nitro]benzimidazole(230 mg, 0.63 mmol) and dipropylethylamine (0.35 mL, 2.0 mmol) inanhydrous DMF (4 mL) under N₂ was addedN-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(610 mg, 1.33 mmol). The reaction mixture was allowed to stir at 85° C.for further 18 hours and then concentrated. The residue was diluted withethylacetate (100 mL) and the orgnic phase was washed with a sat.NaHCO₃, then brine and dried over Na₂SO₄. Evaporation of the solvent andpurification of the residue by radial chromatography on silica gel (1 mmplate, 3:97 MeOH/CH₂Cl₂) gave the desired product (140 mg, 30%) asmixture of two regioisomers.

[0352] Preparation of AMD8926

[0353] The intermediate from above (120 mg, 0.16 mmol) was dissolved inHCl solution (2 N, 3 mL) and the resulting mixture was allowed to refluxfor 4 h. After cooling, the reaction was neutralized by addition ofNaHCO₃, and the aqueous solution was extracted with CHCl₃ (3×50 mL). Thecombined organic extracts were dried over Na₂SO₄ and the solventsevaporated. Purification of the residue by radial chromatography onsilica gel (1 mm plate, 3:3:97 NH₄OH/MeOH/CH₂Cl₂) gave the desiredproduct (46 mg, 53%). ¹H NMR (CDCl₃) δ 1.64-1.68 (m, 2H), 2.07-2.09 (m,2H), 2.28-2.30 (m, 1H), 2.71-2.94 (m, 2H), 3.74 (s, 4H), 3.85 (s, 2H),3.99-4.11 (m, 2H), 4.21-4.28 (m, 1H), 7.13 (dd, 1H, J=5.1, 6.9 Hz),7.20-7.32 (m, 7H), 7.47 (d, 1H, J=7.5 Hz), 7.53-7.66 (m, 2H), 8.14 (dd,1H, J=9.8, 9.8 Hz), 8.45-8.53 (m, 2H), 8.71 (m, 1H); ¹³C NMR (CDCl₃) δ21.78, 23.98, 29.55, 49.06, 53.51, 53.98, 54.85, 61.09, 122.32, 122.71,123.00, 128.69, 129.03, 135.39, 136.80, 138.01, 139.67, 147.13, 149.65,157.55, 160.03. ES-MS m/z 534.3 (M+H). Anal. Calcd. for(C₃₁H₃₁N₇O₂).(1H₂O): C, 67.50; H, 6.03; N, 17.77; Found: C, 67.29; H,5.77; N, 17.77.

Example 64 AMD8929: Preparation ofN-(2-pyridinylmethyl)-N′-[(1H)-5-azabenzimidazol-2-ylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0354] General Procedure for Protection of Benzimidazoles with2-(trimethylsilyl)ethoxymethyl chloride (SEM-Cl)

[0355] To a stirred solution of 5-azabenzimidazole (0.300 g, 2.51 mmol)in anhydrous DMF (5 mL) was added N,N-diisopropylethylamine (0.66 mL,3.80 mmol) followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.54 mL,3.02 mmol). The resultant solution was heated to 80° C. for 2 h thencooled to room temperature. The reaction mixture was poured into brine(20 mL) and diluted with ethyl acetate (30 mL). The phases wereseparated and the aqueous phase was extracted with ethyl acetate (3×15mL). The combined organic extracts were washed with brine (3×5 mL),dried (MgSO₄), and concentrated under reduced pressure. Purification ofthe crude brown oil through a plug of silica gel (CH₂Cl₂/MeOH, 9:1)provided the 1-(2-trimethylsilylethoxymethyl)-5-aza-benzimidazole (0.586g, 93%) as an orange oil.

[0356] General Procedure: Formylation of Benzimidazoles

[0357] To a cold (−40° C.), stirred solution of1-(2-trimethylsilylethoxymethyl)-5-aza-benzimidazole (0.574 g, 2.31mmol) in dry THF (5 mL) was added a 1.7 M solution of tert-butyllithiumin pentane (1.55 mL, 2.63 mmol). The reaction mixture turned deep red.After 20 minutes, DMF (0.50 mL, 6.46 mmol) was added to the reactionmixture and the resultant solution was allowed to warm to roomtemperature overnight. The mixture was poured into saturated aqueousNH₄Cl (25 mL) and diluted with ethylacetate (25 mL). The phases wereseparated and the aqueous phase was extracted with ethyl acetate (3×25mL). The combined organic extracts were dried (MgSO₄) and concentrated.The residual, yellow oil (0.655 g) was used immediately in the nextstep.

[0358] Using general procedure B: A solution ofN-(t-butoxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(0.515 g, 1.12 mmol) and the crude1-[[2-(trimethylsilyl)ethoxy]methyl]-(1H)-5-azabenzimidazole-2-carboxaldehyde(the yellow oil from above) in CH₂Cl₂ (10 mL) were reacted with sodiumtriacetoxyborohydride (0.357 g, 1.68 mmol) for 18 hours. Purification ofthe crude material by column chromatography on silica gel (CH₂Cl₂/MeOH,96:4 to 9:1) provided the desired intermediate as a dark oil.

[0359] The oil from above (0.202 g, 0.28 mmol) in CH₂Cl₂/TFA (2:1, 3 mL)was stirred overnight (16 hours) then concentrated in vacuo. The residuewas diluted with CH₂Cl₂ (25 mL) and 1 N NaOH (40 mL). The aqueous layerwas washed with CH₂Cl₂ (2×25 mL) and the combined organic layers dried(Na₂SO₄), filtered and concentrated in vacuo. Purification of the crudematerial by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,95:4:1) followed by radial chromatography (1 mm plate) on silica gel(CH₂Cl₂/MeOH/NH₄OH, 95:4:1) provided the free base of the title compound(36 mg, 18% 2 steps) as a clear oil.

[0360] Using general procedure D: the free base (36 mg, 0.074 mmol) wasconverted to a hydrobromide salt to give AMD8929 (69 mg, quant.) as awhite solid. ¹H NMR (D₂O) δ 1.79-1.85 (br m, 1H), 2.15-2.26 (br m, 2H),2.36-2.41 (m, 1H), 2.94-2.97 (m, 2H), 3.86 (s, 2H), 4.09 (s, 2H), 4.31(d, 1H, J=15.9 Hz), 4.41 (s, 2H), 4.44 (d, 1H, J=15.9 Hz), 4.59 (dd, 1H,J=10.5, 6.3 Hz), 7.16 (d, 2H, J=7.8 Hz), 7.30 (d, 2H, J=8.1 Hz),7.76-7.81 (m, 3H), 7.95 (d, 1H, J=6.6 Hz), 8.23-8.29 (m, 2H), 8.40 (d,1H, J=6.6 Hz), 8.62 (d, 1H, J=5.7 Hz), 8.68 (dd, 1H, J=5.7, 1.2 Hz),9.05 (s, 1H); ¹³C NMR (D₂O) δ 20.51 (2 carbons), 27.75, 48.24, 51.10,51.51, 55.95, 61.31, 111.24, 125.73, 127.21, 127.28, 129.56, 130.29 (2carbons), 131.00 (2 carbons), 132.49, 133.79, 137.93, 139.14, 139.34,140.56, 145.01, 145.73, 146.12, 146.86, 147.72, 151.66, 162.72. ES-MSm/z 490 (M+H). Anal. Calcd. for C₃₀H₃₁N₇O.4.9HBr.2.3H₂O: C, 38.85; H,4.40; N, 10.57; Br, 42.21. Found: C, 38.97; H, 4.31; N, 10.31; Br,42.12.

Example 65 AMD8931: Preparation ofN-(2-pyridinylmethyl)-N-(4-phenyl-1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine

[0361] To a stirred suspension of sodium hydride (108 mg, 2.70 mmol) inanhydrous DMF (1 mL), at room temperature was added, 4-phenylimidazole(400 mg, 2.78 mmol) in anhydrous DMF (4 mL), and the solution wasstirred at room temperature for 1.5 hours. Sem-Cl (520 uL, 2.94 mmol)was added dropwise to the solution, and the mixture was stirred at roomtemperature for 1 hour. The reaction was quenched with water (10 mL) andthe resulting solution was extracted with EtOAc. The organic phases weredried (Na₂SO₄) and concentrated. The crude material was purified bycolumn chromatography (silica gel, Hexane/EtOAc 50:1) to give theSEM-protected imidazoles [430 mg (58%, major isomer:1-SEM-4-phenylimidazole) and 70 mg (15%, minor isomer:1-SEM-5-phenylimidazole)] as yellow oils.

[0362] To a stirred solution of the Sem-protected 4-phenylimidazole (380mg, 1.39 mmol) in anhydrous THF (7.6 mL) cooled to −40° C. was added, asolution of n-BuLi in hexane (2.5 M, 720 μL, 1.80 mmol), and theresultant solution was stirred at −40° C. for 20 minutes. To thissolution was added, DMF (323 μL, 4.17 mmol) and the mixture was allowedto stir for 4 hours at −40° C. The reaction was quenched with NH₄Cl (5mL) and the mixture was extracted with EtOAc (3×80 mL). The combinedorganic phases were dried (Na₂SO₄) and concentrated to afford the SEMprotected 4-phenylimidazole-2-carboxaldehyde (411 mg, 98%) as a yellowsolid.

[0363] Using general procedure B: To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(244 mg, 0.45 mmol) in THF (5 mL), at room temperature, was added thealdehyde from above (150 mg, 0.50 mmol), glacial acetic acid (250 μL)and NaBH(OAc)₃ (286 mg, 1.35 mmol), and the resultant solution wasstirred at room temperature for 1 hour. The solution was diluted withEtOAc (100 mL), filtered through celite, and concentrated in vacuo. Thecrude material was purified by column chromatography (silica gel,CH₂CH₂/MeOH/NH₄OH 98:1:1) to afford the desired product (266 mg, 71%yield) as a yellow foam.

[0364] The foam from above (190 mg, 0.23 mmol) was dissolved in 6 M HClsolution (6 mL), and the resultant solution was stirred at 50° C. for 3hours. The mixture was neutralized with K₂CO₃, and extracted with EtOAc(3×50 mL). The combined organic phases were dried (Na₂SO₄) andconcentrated in vacuo. The crude material was purified by columnchromatography (silica gel, CH₂CH₂/MeOH/NH₄OH 98:1:1) to afford thedesired product (141 mg, 88%) as a yellow foam.

[0365] Using general procedure C: The intermediate from above (135 mg,0.19 mmol) was reacted with thiophenol (57.3 μL, 0.56 mmol) and K₂CO₃(128 mg, 0.93 mmol) in DMF (1.9 mL). Purification of the crude materialby column chromatography on silica gel (CH₂CH₂/MeOH/NH₄OH 48:1:1) gaveAMD8931 (61 mg) as a white foam. ¹H NMR (CDCl₃) δ 1.50-1.71 (m, 1H),1.75-2.03 (m, 3H), 2.22-2.23 (m, 2H), 2.68-2.89 (m, 2H), 3.68 (s, 2H),3.76 (s, 2H), 3.82 (s, 1H), 3.87 (s, 2H), 4.06 (d, 2H, J=16.2 Hz),7.10-7.42 (m, 12H), 7.59 (t, 1H, J=7.5 Hz), 7.72 (br s, 2H), 8.52 (d,1H, J==6.6 Hz), 8.53 (br s, 1H); ¹³C NMR (CDCl₃) δ 21.29, 23.18, 29.26,47.99, 53.19, 53.64, 54.48, 59.75, 121.85, 122.12, 122.32, 124.52,126.12, 128.15, 128.57, 134.67, 136.36, 137.06, 138.29, 138.97, 147.09,149.23, 157.71, 159.79.ES-MS m/z 515 (M+H). Anal. Calcd. forC₃₃H₃₄N₆.0.9H₂O: C, 74.66; H, 6.80; N, 15.83. Found: C, 74.53; H, 6.61;N, 15.86.

Example 66 AMD8783: Preparation ofN-(2-pyridinylmethyl)-N′-[2-(2-pyridinyl)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0366] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(276 mg, 0.51 mmol) and anhydrous K₂CO₃ (750 mg, 5.4 mmol) in anhydrousDMF (3 ml) under N₂ was added 2-(2-methanesulfonylethyl)pyridine (450mg, 2.2 mmol). The reaction mixture was allowed to stir at 85° C. forfurther 18 hours and then concentrated. The residue was diluted withethylacetate (100 mL) and the solution was washed with saturated aqueousNaHCO₃ then brine and dried over Na₂SO₄. Evaporation of the solvent andpurification of the crude material by column chromatography on silicagel (1.5×20 cm, 50:50 EtOAc/CH₂Cl₂) gave the desired intermediate (100mg, 32%) as a yellow oil.

[0367] Using general procedures C and D: the intermediate from above wasreacted with anhydrous K₂CO₃ (137 mg, 0.99 mmol) and thiophenol (51 μl,0.49 mmol) in DMF (3 ml). Purification of the crude material by radialchromatography on silica gel (1 mm plate, 3:3:94 MeOH/NH₄OH/CH₂Cl₂) gavethe free base of the title compound (90 mg, 76%) as a light yellow oil.Conversion of the free base (90 mg, 0.19 mmol) to the hydrobromide saltgave AMD8783 (130 mg). ¹H NMR (CD₃OD) δ 1.88-1.89 (m, 1H), 2.11-2.18 (m,2H), 2.42-2.44 (m, 1H), 2.98-3.03 (m, 2H), 3.20-3.40 (m, 1H), 3.46-3.66(m, 3H), 4.05 (d, 1H, J=13.8 Hz), 4.17 (d, 1H, J=13.8 Hz), 4.44 (s, 2H),4.54-4.57 (m, 1H), 4.65 (s, 2H), 7.63 (d, 2H, J=8.1 Hz), 7.71 (d, 2H,J=8.1 Hz), 7.76-7.85 (m, 2H), 7.94-8.06 (m, 3H), 8.19 (d, 1H, J=7.8 Hz),8.34 (dd, 1H, J=7.2, 7.2 Hz), 8.56 (ddd, 1H, J=1.2, 7.8, 7.8 Hz), 8.74(dd, 2H, J=5.6, 5.6 Hz), 8.83 (b, 1H); ¹³C NMR (CD₃OD) δ 22.06, 28.97,33.40, 52.18, 52.63, 56.21, 60.83, 67.31, 126.72, 127.04, 127.70,127.90, 129.59, 132.09, 132.42, 139.65, 140.66, 142.82, 142.96, 144.70,147.11, 147.51, 148.70, 149.83, 153.35, 155.77. ES-MS m/z 464.2 (M+H).Anal. Calcd. for C₃₀H₃₃N₅.4.0HBr.3.0H₂O: C, 42.83; H, 5.15; N, 8.32; Br,37.99. Found: C, 43.04; H, 5.18; N, 8.14; Br, 37.75.

Example 67 AMD8764: Preparation ofN-(2-pyridinylmethyl)-N′-(2-benzoxazolyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0368] A solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(260 mg, 0.48 mmol) and 2-chlorobenzoxazole (115 mg, 0.749 mmol) inCH₃CN (2.5 mL) was heated at reflux under nitrogen atmosphere for 3hours. Saturated NaHCO₃(aq) (10 mL) was added, and the mixture wasextracted with CH₂Cl₂ (1×10 mL, 2×5 mL). The combined organic extractswere dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby chromatography on silica gel using 70%-90% EtOAc/hexanes then onreverse phase C-18 using 7:3 to 9:1 MeOH/H₂O to give a colourless solid(101 mg, 32%).

[0369] Using general procedures C and D: The intermediate from above (92mg, 0.14 mmol) was reacted with thiophenol (0.045 mL, 0.44 mmol) andK₂CO₃ (80 mg, 0.58 mmol) in CH₃CN (2.2 mL) under nitrogen atmosphere at40° C. for 1 hour. Brine (15 mL) was added, and the mixture wasextracted with CH₂Cl₂ (1×20 mL, 2×10 mL). The combined organic extractswere dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby column chromatography on neutral alumina using CH₂Cl₂ and 10%MeOH/CH₂Cl₂ to give a light yellow oil (47 mg, 71%). Conversion to thehydrobromide salt gave AMD8764 as a colourless solid (59 mg, 74%). ¹HNMR (D₂O) δ 1.90-2.26 (m, 4H), 3.03 (br s, 2H), 4.37 (s, 2H), 4.58 (s,2H), 4.84 (s, 1H), 4.81 (d, 1H, J=18 Hz), 5.02 (d, 1H, J=18 Hz), 5.82(t, 1H, J=9 Hz), 7.21-7.45 (m, 8H), 7.83 (m, 3H), 8.33 (m, 3H), 8.73 (d,1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 20.40, 26.65, 27.43, 48.62, 51.11, 51.36,57.16, 110.49, 115.69, 123.29, 125.59, 126.29, 127.01, 127.10, 128.85,130.24, 130.95, 138.07, 138.95, 140.02, 140.74, 144.48, 146.08, 147.23,148.02, 148.16, 148.27, 161.78. ES-MS m/z 476 (M+H). Anal. Calcd. forC₃₀H₂₉N₅O.4.2HBr.3.9H₂O: C, 40.68; H, 4.67; N, 7.91; Br, 37.89. Found:C, 40.80; H, 4.55; N, 7.81; Br, 37.71.

Example 68 AMD8780: Preparation ofN-(2-pyridinylmethyl)-N′-(trans-2-aminocyclohexyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0370] N-(2-nitrobenzenesulfonyl)-7-azabicyclo[4.1.0]heptane(N-(2-nitrobenzenesulfonyl)-1,2-cyclohexeneaziridine).

[0371] A solution of trans-2-aminocyclohexanol hydrochloride (2.50 g,16.5 mmol) and 2-nitrobenzenesulfonyl chloride (3.66 g, 16.5 mmol) inCH₂Cl₂ (35 mL) was cooled in an ice bath under nitrogen atmosphere whileEt₃N (5.10 mL, 36.6 mmol) was added. The mixture was heated at refluxfor 35 minutes, then concentrated in vacuo. Water (25 mL) was added tothe residue, and the mixture was extracted with EtOAc (50 mL). Theorganic extract was washed with brine (3×15 mL), then dried (MgSO₄) andconcentrated in vacuo to give a grey solid (5.73 g).

[0372] A solution of the solid from above and Et₃N (2.8 mL, 20 mmol) inCH₂C]₂ (30 mL) was stirred at −40° C. under nitrogen atmosphere whilemethanesulfonyl chloride (1.4 mL, 18 mmol) was added. The mixture wasstirred at −40° C. for 10 minutes, then the cold bath was removed andstirring was continued at room temperature for 30 minutes and thesolution was then concentrated in vacuo. Water (25 mL) and saturatedNaHCO₃(aq) (25 mL) were added to the residue, and the mixture wasextracted with EtOAc (1×20 mL, 3×10 mL). The combined organic extractswere dried (MgSO₄) and concentrated in vacuo to give the crude mesylateas a light yellow solid (6.12 g).

[0373] The crude mesylate (258 mg, 0.682 mmol) was stirred as asuspension in benzene (3 mL) at room temperature while a solution of 85%KOH (230 mg, 3.5 mmol) in H₂O (1 mL) was added. The mixture was stirredfor 30 minutes, and additional benzene (10 mL) was added. The organicphase was separated and washed with brine (10 mL), then dried (MgSO₄)and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (25% EtOAc/hexanes) to give the desiredaziridine as colorless crystals (141 mg, 72% over 3 steps).

[0374] A solution of the aziridine from above (92 mg, 0.33 mmol),N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(213 mg, 0.392 mmol) and Et₃N (0.01 mL, 0.07 mmol) in THF (1.1 mL) washeated at 60° C. under nitrogen atmosphere for 48 hours. The solutionwas diluted with EtOAc (15 mL) and washed with brine (10 mL). Theaqueous phase was extracted with EtOAc (2×10 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (70% EtOAc/hexanes) togive a yellow solid (155 mg, 58%).

[0375] Using general procedures C and D: The intermediate from above(111 mg, 0.134 mmol) was reacted thiophenol (0.085 mL, 0.83 mmol) andK₂CO₃ (150 mg, 1.08 mmol) in CH₃CN (2.7 mL) under nitrogen atmosphere at40° C. for 22 hours. Brine (15 mL) was added, and the mixture wasextracted with CH₂Cl₂ (3×10 mL). The combined organic extracts weredried (MgSO₄) and concentrated in vacuo. The residue was purified bycolumn chromatography on neutral alumina (CH₂Cl₂ then 10% MeOH/CH₂Cl₂)to give the free base of the title compound as a yellow oil (53 mg,87%). Conversion to the hydrobromide salt followed by re-preciptation ofthe intermediate solid from methanol/ether gave AMD8780 as a lightyellow solid (46 mg, 52%). ¹H NMR (D₂O) mixture of two diastereomers: δ1.26-2.49 (m, 24H), 2.81-3.18 (m, 6H), 3.40-3.56 (m, 2H), 3.71-3.96 (m,4H), 4.19 (s, 2H), 4.32 (s, 2H), 4.43 (s, 2H), 4.45 (m, 1H), 4.47 (s,2H), 7.23 (br s, 6H), 7.36 (m, 5H), 7.54 (m, 1H), 7.70 (m, 4H), 8.11 (m,4H), 8.50 (d, 1H, J=4.8 Hz), 8.65 (d, 1H, J=4.8 Hz); ¹³C NMR (D₂O) δ14.53, 19.53, 20.94, 23.89, 25.09, 25.35, 27.50, 27.95, 29.26, 30.94,31.40, 47.91, 49.54, 50.96, 51.12, 51.40, 52.78, 56.61, 62.56, 63.63,66.47, 67.70, 125.25, 125.78, 125.96, 126.06, 126.15, 129.83, 130.17,130.68, 130.77, 139.13, 139.38, 139.70, 140.32, 140.81, 142.14, 142.27,147.40, 147.63, 148.54, 151.21, 151.98. ES-MS m/z 456 (M+H). Anal.Calcd. for C₂₉H₃₇N₅.4.0HBr.3.9H₂O: C, 41.00; H, 5.79; N, 8.24; Br,37.62. Found: C, 41.08; H, 5.50; N, 8.05; Br, 37.58.

Example 69 AMD8818: Preparation ofN-(2-pyridinylmethyl)-N′-(2-phenylethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0376] A solution of 2-phenylethanol (510 mg, 4.17 mmol) andp-toluenesulfonyl chloride (874 mg, 4.58 mmol) in CH₂Cl₂ (15 mL) wasstirred in an ice bath while Et₃N (0.70 mL, 5.0 mmol) was added. Thecold bath was removed, and the solution was heated at reflux undernitrogen atmosphere for 42 hours. The solution was washed with 10%HCl(aq) (10 mL), saturated NaHCO₃(aq) (10 mL), and brine (5 mL), thendried (MgSO₄) and concentrated in vacuo to give the tosylate as a yellowoil (783 mg, 68%).

[0377]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(355 mg, 0.653 mmol), the tosylate from above (356 mg, 1.29 mmol) andK₂CO₃ (271 mg, 1.96 mmol) were heated at reflux in CH₃CN (3 mL) undernitrogen atmosphere for 19 hours. The mixture was diluted with EtOAc (15mL) and washed with brine (10 mL), then dried (MgSO₄) and concentratedin vacuo. The residue was purified by column chromatography on silicagel (60% THF/hexanes) to give a yellow oil (241 mg, 57%).

[0378] Using General procedures C and D: The oil from above (225 mg,0.347 mmol) was reacted with thiophenol (0.11 mL, 1.1 mmol) and K₂CO₃(192 mg, 1.39 mmol) in CH₃CN (7 mL) with stirring under nitrogenatmosphere at 40° C. for 1.5 hours. Brine (15 mL) was added, and themixture was extracted with CH₂Cl₂ (3×10 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography on neutral alumina (CH₂Cl₂ then 10%MeOH/CH₂Cl₂) to give the free base of the title compound (79 mg, 49%) asa yellow oil. Conversion of the free base (74 mg, 0.16 mmol) to thehydrobromide salt followed by re-preciptation of the intermediate solidfrom methanol/ether gave AMD8818 (114 mg, 86%) as a light yellow solid.¹H NMR (D₂O) δ 1.82 (m, 1H), 2.04-2.19 (m, 2H), 2.50 (m, 1H), 2.85-3.01(m, 4H), 3.37 (br s, 1H), 3.66 (br s, 1H), 4.32 (m, 2H), 4.42 (s, 2H),4.58 (s, 2H), 4.76 (m, 1H), 7.09 (m, 2H), 7.29-7.48 (m, 8H), 7.69-7.88(m, 3H), 8.31 (m, 2H), 8.71 (d, 1H); ¹³C NMR (D₂O) δ 20.40, 20.91,27.23, 31.23, 48.72, 51.29, 52.20, 54.75, 62.22, 124.74, 126.99, 128.01,129.45, 129.62, 131.35, 132.00, 132.36, 135.73, 135.94, 139.85, 144.34,146.17, 146.50, 147.23, 148.49. ES-MS m/z 463 (M+H). Anal. Calcd. forC₃₁H₃₄N₄.3.9HBr.2.9H₂O: C, 44.84; H, 5.30; N, 6.75; Br, 37.53. Found: C,44.77; H, 5.04; N, 6.59; Br, 37.55.

Example 70 AMD8829: Preparation ofN-(2-pyridinylmethyl)-N′-(3-phenylpropyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0379] A solution of 3-phenylpropanol (510 mg, 3.74 mmol) andp-toluenesulfonyl chloride (770 mg, 4.04 mmol) in CH₂Cl₂ (15 mL) wasstirred in an ice bath while Et₃N (0.61 mL, 4.4 mmol) was added. Thecold bath was removed, and the solution was heated at reflux undernitrogen atmosphere for 19 hours. The solution was washed with 10%HCl(aq) (5 mL), saturated NaHCO₃(aq) (10 mL), and brine (5 mL), thendried (MgSO₄) and concentrated in vacuo to give the tosylate as a yellowoil (893 mg, 82%).

[0380]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(312 mg, 0.574 mmol), the tosylate from above (320 mg, 1.10 mmol) andK₂CO₃ (250 mg, 1.81 mmol) were heated at reflux in CH₃CN (2.5 mL) undernitrogen atmosphere for 24 hours. The mixture was diluted with EtOAc (15mL) and washed with brine (10 mL), then dried (MgSO₄) and concentratedin vacuo. The residue was purified by column chromatography on silicagel (70% THF/hexanes) to give a yellow oil (261 mg, 69%).

[0381] Using general procedures C and D: The oil (257 mg, 0.388 mmol)was reacted with thiophenol (0.12 mL, 1.2 mmol), and K₂CO₃ (215 mg, 1.56mmol) in CH₃CN (7.5 mL) under nitrogen atmosphere with stirring at 40°C. for 1 hour. Brine (10 mL) was added, and the mixture was extractedwith CH₂Cl₂ (3×10 mL). The combined organic extracts were dried (MgSO₄)and concentrated in vacuo. The residue was purified by columnchromatography on neutral alumina (CH₂Cl₂ then 10% MeOH/CH₂Cl₂) to givethe free base of the title compound (97 mg, 52%) as a yellow oil.Conversion of the free base (94 mg, 0.20 mmol) to the hydrobromide saltfollowed by re-precipitation of the crude material from methanol/ethergave AMD8829 (141 mg, 87%) as a yellow solid. ¹H NMR (D₂O) δ 1.75-2.12(m, 5H), 2.35 (m, 1H), 2.56 (m, 2H), 2.80 (m, 2H), 3.13 (br s, 1H), 3.29(br s, 1H), 4.24 (m, 2H), 4.41 (s, 2H), 4.56 (s, 2H), 4.76 (m, 1H),7.09-7.35 (m, 6H), 7.50 (br s, 4H), 7.64 (d, 1H, J=7.5 Hz), 7.85 (m,2H), 8.34 (m, 1H), 8.45 (br s, 1H), 8.73 (d, 1H, J=5.4); ¹³C NMR (D₂O) δ20.32, 20.94, 26.58, 27.36, 32.01, 48.50, 51.31, 62.44, 124.75, 126.90,127.16, 127.25, 128.82, 129.19, 131.23, 131.82, 132.12, 135.75, 139.65,140.47, 144.80, 145.89, 146.97, 148.66. ES-MS m/z 477 (M+H). Anal.Calcd. for C₃₂H₃₆N₄.3.9HBr.1.8H₂O: C, 46.61; H, 5.32; N, 6.79; Br,37.79. Found: C, 46.47; H, 5.11; N, 6.64; Br, 37.93.

Example 71 AMD8839: Preparation ofN-(2-pyridinylmethyl)-N′-(trans-2-aminocyclopentyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0382] N-(2-nitrobenzenesulfonyl)-6-azabicyclo[3.1.0]hexane(N-(2-nitrobenzenesulfonyl-1,2-cyclopenteneaziridine).

[0383] A solution of (1S,2S)-2-benzyloxycyclopentylamine (417 mg, 2.18mmol) and 2-nitrobenzenesulfonyl chloride (531 mg, 2.40 mmol) in CH₂Cl₂(10 mL) was cooled in an ice bath under nitrogen atmosphere while Et₃N(0.36 mL, 2.6 mmol) was added. The mixture was heated at reflux for 1hour, then washed with H₂O (10 mL). The aqueous phase was extracted withCH₂Cl₂ (5 mL). The combined organic phases were dried (MgSO₄) andconcentrated in vacuo to give the crude sulfonamide as a dark oil (787mg).

[0384] A solution of the crude sulfonamide (675 mg, 1.79 mmol) and TMSI(0.64 mL, 4.5 mmol) in CH₃CN (9 mL) was heated at 40° C. under nitrogenatmosphere for 21 hours. Saturated NaHCO₃(aq) (15 mL) was added, and themixture was extracted with CH₂Cl₂ (1×15 mL, 2×10 mL). The combinedorganic extracts were dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (50%EtOAc/hexanes) to give the alcohol as a yellow oil (424 mg, 80% over 2steps).

[0385] A solution of the alcohol (464 mg, 1.62 mmol) and Et₃N (0.27 mL,1.9 mmol) in CH₂Cl₂ (8 mL) was stirred at −78° C. under nitrogenatmosphere while methanesulfonyl chloride (0.14 mL, 1.8 mmol) was added.The cold bath was removed, and stirring was continued at roomtemperature for 20 minutes and the solution was concentrated in vacuo.Ethyl acetate (20 mL) was added, and the mixture was washed withsaturated NaHCO₃(aq) (15 mL) and brine (15 mL). The organic phase wasdried (MgSO₄) and concentrated in vacuo to give the mesylate as a yellowoil (725 mg). This was used without further purification in the nextstep.

[0386] A solution of the crude mesylate in benzene (6 mL) was stirred atroom temperature while a solution of 85% KOH (530 mg, 8.0 mmol) in H₂O(2.5 mL) was added. The mixture was stirred for 45 minutes, and benzene(20 mL) was added to the mixture. The organic phase was separated andwashed with brine (10 mL), then dried (MgSO₄) and concentrated in vacuo.The residue was purified by chromatography on silica gel (25%EtOAc/hexanes) to give the desired aziridine as yellow crystals (293 mg,67% over 2 steps).

[0387] A solution of the aziridine from above (138 mg, 0.514 mmol),N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(340 mg, 0.625 mmol), and Et₃N (0.04 mL, 0.29 mmol) in THF (1.7 mL) washeated at 60° C. under nitrogen atmosphere for 48 hours. The solutionwas diluted with EtOAc (15 mL) and washed with brine (10 mL). Theaqueous phase was extracted with EtOAc (2×10 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (50% THF/hexanes) togive a yellow solid (203 mg, 49%).

[0388] Using general procedures C and D: the solid (186 mg, 0.229 mmol)was reacted with thiophenol (0.14 mL, 1.4 mmol) and K₂CO₃ (253 mg, 1.83mmol) with stirring in CH₃CN (4.6 mL) under nitrogen atmosphere at 40°C. for 20 hours. Brine (10 mL) was added, and the mixture was extractedwith CH₂Cl₂ (3×10 mL). The combined organic extracts were dried (MgSO₄)and concentrated in vacuo. The residue was purified by columnchromatography on neutral alumina (CH₂Cl₂ then 10% MeOH/CH₂Cl₂) to givethe free base of the title compound (91 mg, 90%) as a yellow oil.Conversion of the free base (87 mg, 0.20 mmol) to the hydrobromide saltfollowed by re-precipitation of the crude material from methanol/ethergave AMD8839 (108 mg, 66%) as a light yellow solid. ¹H NMR (D₂O):mixture of diastereomers: δ 1.54-2.52 (m, 20H), 2.88 (m, 4H), 3.23-3.92(m, 8H), 4.21 (s, 2H), 4.34 (s, 2H), 4.37 (m, 1H), 4.46 (s, 2H), 4.53(s, 2H), 7.21 (m, 4H), 7.43 (m, 8H), 7.71-7.83 (m, 5H), 7.99 (m, 1H),8.23 (m, 2H), 8.46 (d, 1H), 8.70 (d, 1H, J=6.0 Hz); ¹³C NMR (D₂O) δ20.72, 20.93, 22.04, 22.12, 22.71, 23.96, 26.18, 27.58, 27.67, 28.41,28.75, 47.32, 48.88, 51.09, 51.33, 52.24, 54.43, 55.93, 56.88, 62.44,66.92, 72.46, 124.89, 125.53, 126.77, 129.45, 130.11, 130.60, 130.81,130.90, 138.40, 139.00, 139.26, 139.60, 140.05, 140.34, 143.65, 143.81,146.56, 146.89, 147.40, 147.63, 151.93, 152.93. ES-MS m/z 442 (M+H).Anal. Calcd. for C₂₈H₃₅N₅.4.3HBr.2.3H₂O: C, 40.47; H, 5.32; N, 8.43; Br,41.35. Found: C, 40.66; H, 5.22; N, 8.27; Br, 41.13.

Example 72 AMD8726: Preparation ofN-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-glycinamide(hydrobromide salt)

[0389] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(218 mg, 0.40 mmol) in dry CH₂Cl₂ (5 mL) was addedN-(tert-butoxycarbonyl)glycine (85 mg, 0.49 mmol),N,N-diisopropylethylamine (0.23 mL, 1.32 mmol), 1-hydroxybenzotriazolehydrate (73 mg, 0.54 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (EDC) (105 mg, 0.55 mmol) and the mixture was stirredat room temperature for 17 h. The reaction mixture was diluted withCH₂Cl₂ (10 mL) and brine (15 mL) and the aqueous layer was separated andextracted with CH₂Cl₂ (2×10 mL). The combined organic phases were dried(MgSO₄), filtered and evaporated in vacuo to give the crude product asan orange oil. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH, 95:5) gave the intermediate amide (185 mg, 66%) as ayellow foam.

[0390] To a stirred solution of the amide from above (185 mg, 0.26 mmol)in dry CH₃CN (5 mL) was added thiolphenol (0.12 mL, 1.2 mmol) andpowdered potassium carbonate (196 mg, 1.42 mmol) and the mixture wasstirred at room temperature for 16 h. The reaction mixture wasconcentrated in vacuo and partitioned between CH₂Cl₂ (15 mL) and water(15 mL). The aqueous layer was separated and extracted with CH₂Cl₂ (2×10mL) and the combined organic phases were dried (MgSO₄), filtered andevaporated in vacuo to give the crude product as a yellow oil.Purification by column chromatography on silica gel (CH₂Cl₂/MeOH, 95:5followed by 9:1) afforded the desired amine (85 mg, 62%) as a paleyellow oil.

[0391] To a stirred solution of the free base (58 mg, 0.11 mmol) inglacial acetic acid (1 mL) was added a saturated solution of HBr inacetic acid (1 mL) and the mixture was stirred at room temperature for 1h. Diethyl ether (20 mL) was added resulting in the formation of a whiteprecipitate. The solid was allowed to settle to the bottom of the flaskand the supernatant solution was decanted off. The solid was washed bydecantation with ether (4×10 mL) and the remaining traces of solventremoved by evaporation under reduced pressure followed by drying invacuo overnight to give AMD 8726 as an off-white solid (87 mg, 94%). ¹HNMR (D₂O) mixture of rotational isomers δ 1.64-2.20 (m) and 2.36-2.52(m) (total 4H), 2.89-3.10 (m, 2H), 4.18 (d, J=16.5 Hz) and 4.30-4.58 (m)(total 7H), 4.70-4.85 (m, overlap with HOD) and 5.46-5.51 (m) (total2H), 7.17 (d, J=8.1 Hz) and 7.36 (d, J=8.1 Hz) and 7.46 (d, J=8.1 Hz)and 7.53 (d, J=8.1 Hz) (total 4H), 7.82-7.85 (m) and 8.28-8.33 (m) and8.45 (d, J=5.7 Hz) and 8.75 (d, J=5.7 Hz) (total 7H); ¹³C NMR (D₂O)mixture of rotational isomers δ 20.55, 20.84, 26.49, 27.53, 27.67,41.38, 41.52, 47.58, 48.97, 49.14, 51.25, 51.38, 55.43, 56.03, 125.63,126.62, 126.74, 128.26, 128.91, 129.70, 130.80, 131.16, 136.96, 138.66,139.56, 139.78, 140.26, 141.13, 143.41, 143.67, 146.72, 146.91, 147.92,147.99, 148.51, 149.53, 168.40, 168.86. ES-MS m/z 416 (M+H). Anal.Calcd. for C₂₅H₂₉N₅O.4.0HBr.2.1H₂O1.2CH₃CO₂H: C, 38.60; H, 4.98; N,8.20; Br, 37.78. Found: C, 38.59; H, 4.88; N, 8.22; Br, 37.77.

Example 73 AMD8738: Preparation ofN-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-alaninamide(hydrobromide salt)

[0392] To a solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(251 mg, 0.46 mmol) and N-(tert-butoxycarbonyl)-L-alanine (97 mg, 0.51mmol) in CH₂Cl₂ (5 mL) was added N,N-diisopropylethylamine (0.24 mL,1.38 mmol), 1-hydroxybenzotriazole hydrate (81 mg, 0.60 mmol) and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (116 mg, 0.61mmol) and the mixture was stirred at room temperature for 15 hours. Thereaction was worked-up as described above to give the crude amide as amixture of diastereomers. Purification and separation of thediastereomers was accomplished by column chromatography on silica gel(EtOAc) to afford a low polarity diastereomer (78 mg, 24%) and a highpolarity diastereomer (48 mg, 15%).

[0393] Using procedures C and D: the less polar diastereomer (78 mg,0.11 mmol) was reacted with thiophenol (50 μL, 0.49 mmol) and potassiumcarbonate (83 mg, 0.60 mmol) in CH₃CN (5 mL) for 2 hours. The crudematerial was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 95:5 to 9:1) to give the corresponding free base ofAMD8738 (33 mg, 57%) as a clear oil. The oil was converted to thehydrobromide salt to give AMD8738 (49 mg, 89%) as a pale yellow solid.¹H NMR (D₂O) single diastereomer, mixture of rotational isomers δ 1.61(d, J=7.1 Hz) and 1.69 (d, J=7.1 Hz) (total 3H), 1.90-2.13 (m) and2.34-2.48 (m) (total 4H), 2.88-2.91 (m) and 2.97-3.00 (m) (total 2H),4.27-4.49 (m) and 4.67-5.02 (m, overlap with HOD) (total 7H), 5.02-5.08(m) and 5.64-5.67 (m) (total 1H), 7.14 (d, J=8.1 Hz) and 7.37 (d, J=8.1Hz) and 7.50 (br s) (total 4H), 7.71-7.86 (m) and 8.14-8.17 (m) and 8.26(d, J=8.1 Hz) and 8.35 (d, J=8.1 Hz) and 8.42 (t, J=5.1 Hz) and 8.66 (brs) (total 7H); ¹³C NMR (D₂O) single diastereomer, mixture of rotationalisomers δ 16.75, 16.82, 20.39, 20.49, 26.34, 27.54, 27.62, 28.01,47.61,48.43, 48.55, 49.13, 49.36, 51.14, 51.18, 52.77, 56.01, 56.42,125.38, 126.30, 126.38, 126.46, 126.60, 127.65, 129.67, 130.86, 131.13,136.46, 138.50, 139.39, 139.48, 140.66, 141.25, 142.77, 143.08, 147.04,147.26, 147.57, 147.84, 148.06, 148.22, 148.49, 149.87, 171.35, 172.63.ES-MS m/z 430 (M+H). Anal. Calcd. forC₂₆H₃₁N₅O.4.3HBr.1.9H₂O.1.2CH₃CO₂H: C, 38.60; H, 5.01; N, 7.92; Br,38.88. Found: C, 38.45; H, 4.88; N, 7.91; Br, 39.10.

Example 74 AMD8749: Preparation ofN-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-aspartamide(hydrobromide salt)

[0394] A solution of N-(tert-butoxycarbonyl)-L-aspartic acid β-t-butylester dicyclohexylammonium salt (500 mg, 1.06 mmol) in EtOAc (25 mL) waswashed with a 10% aqueous citric acid solution (2×25 mL) and brine (1×25mL). The organic phase was dried (MgSO₄), filtered and concentrated togive the corresponding free acid (305 mg) as a clear oil.

[0395] To a solution ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(420 mg, 0.92 mmol) and N-(tert-butoxycarbonyl)-L-aspartic acidβ-t-butyl ester (305 mg, 1.06 mmol) in 1,2-dichloroethane (6 mL) wasadded N,N-diisopropylethylamine (0.50 mL, 2.88 mmol),1-hydroxybenzotriazole hydrate (175 mg, 1.30 mmol) and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (250 mg, 1.30mmol) and the reaction mixture was stirred at room temperature for 18hours. The reaction was worked-up as described above and the crudematerial was purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 98:2) to give the desired amide (145 mg, 23%) as a mixtureof diastereomers.

[0396] Using general procedure D: the intermediate from above (47 mg,0.08 mmol) was converted to the hydrobromide salt to give AMD8749 (73mg, 89%) as a light brown solid. ¹H NMR (D₂O) mixture of diastereomers,mixture of rotational isomers: δ 1.69-1.84 (br m) and 1.98-2.04 (br m)and 2.10-2.20 (br m) and 2.45-2.49 (br m) (total 4H), 2.96-3.01 (m) and3.00 (d, J=6.6 Hz) and 3.08 (d, J=4.2 Hz) and 3.13-3.18 (m) (total 4H),4.37 (s) and 4.42 (s) and 4.51 (s) and 4.52 (s) and 4.69-4.72 (m) and4.79-4.88 (m, overlap with HOD) and 4.92-5.01 (m) and 5.07-5.14 (m) and5.18-5.22 (m) and 5.30-5.38 (m) and 5.71-5.77 (m) (total 8H), 7.19 (d,J=7.8 Hz) and 7.41 (d, J=7.8 Hz) and 7.50-7.58 (m) (total 5H), 7.67-7.73(m) and 7.79-7.89 (m) and 8.13-8.19 (m) and 8.30-8.39 (m) and 8.44 (t,J=5.7 Hz) and 8.50 (d, J=6.0 Hz) and 8.70 (d, J=4.6 Hz) (total 6H); ¹³CNMR (D₂O) mixture of diastereomers, mixture of rotational isomers: δ20.38, 20.56, 20.66, 20.88, 26.37, 26.75, 27.64, 29.42, 34.87, 35.34,35.49, 48.21, 48.58, 48.81, 51.36, 52.88, 53.02, 56.28, 56.68, 56.96,125.62, 126.75, 127.00, 127.13, 127.22, 127.92, 129.43, 129.62, 130.93,131.12, 131.28, 131.36, 136.71, 138.48, 139.51, 139.64, 140.04, 140.75,141.39, 144.39, 144.45, 144.71, 146.06, 146.24, 146.31, 147.20, 147.31,147.86, 148.04, 148.62, 149.54, 149.64, 169.30, 169.63, 172.62, 172.90.ES-MS m/z 474 (M+H). Anal. Calcd. forC₂₇H₃₁N₅O₃.4.1HBr.1.8H₂O.1.8CH₃CO₂H: C, 38.86; H, 4.89; N, 7.40; Br,34.64. Found: C, 38.99; H, 4.77; N, 7.47; Br, 34.52.

Example 75 AMD8750: Preparation ofN-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-pyrazinamide(hydrobromide salt)

[0397] To a stirred solution ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(183 mg, 0.40 mmol) in dry CH₂Cl₂ (5 mL) was added 2-pyrazinecarboxylicacid (68 mg, 0.55 mmol), N,N-diisopropylethylamine (0.21 mL, 1.21 mmol),1-hydroxybenzotriazole hydrate (81 mg, 0.60 mmol) and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (115 mg, 0.60mmol) and the mixture was stirred at room temperature for 20 hours.Following standard work-up procedures, the crude material was purifiedby column chromatography on silica gel (CH₂Cl₂/MeOH, 98:2 followed by95:5) to give the desired amide (131 mg, 58%) as a colorless oil.

[0398] Using general procedure D: the oil from above (105 mg, 0.19 mmol)was converted to the hydrobromide salt with simultaneous deprotection ofthe BOC group to give AMD8750 (127 mg, 87%) as a light yellow solid. ¹HNMR (D₂O) mixture of rotational isomers δ 1.71-1.88 (br m, 1H),2.00-2.19 (br m, 2H), 2.28-2.40 (br m, 1H), 2.95-2.97 (br m) and3.02-3.04 (m) (total 2H), 4.39 (s) and 4.43 (s) and 4.56-4.67 (m) and4.62 (s) and 4.66 (s) and 4.76-5.05 (m, overlap with HOD) and 5.59-5.71(m) and 5.75-5.84 (m) (total 7H), 7.31-7.46 (m, 4H), 7.84-7.90 (m) and7.94-7.98 (m) and 8.01 (d, J=8.1 Hz) and 8.36 (t, J=7.8 Hz) and 8.47 (t,J=8.1 Hz) and 8.51-8.55 (m) and 8.68-8.71 (m) and 8.73 (s) and 8.80 (brs) and 9.13 (s) (total 1OH); ¹³C NMR (D₂O) mixture of rotational isomersδ 20.43, 20.59, 26.71, 27.57, 27.75, 28.05, 48.12, 48.21, 51.45, 51.59,53.70, 56.43, 58.13, 125.74, 126.40, 127.53, 127.71, 127.74, 128.31,129.39, 129.49, 130.43, 130.83, 131.00, 138.21, 138.58, 139.77, 140.14,140.23, 141.21, 143.99, 144.30, 145.29, 145.44, 145.65, 145.82, 146.37,146.59, 146.92, 148.07, 148.18, 148.41, 149.48, 169.00, 170.05. ES-MSm/z 465 (M+H). Anal. Calcd. for C₂₈H₂₈N₆O.4.0HBr.1.7H₂O.1.5CH₃CO₂H: C,40.97; H, 4.59; N, 9.25; Br, 35.16. Found: C, 40.97; H, 4.62; N, 9.27;Br, 35.23.

Example 76 AMD8740: Preparation ofN-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-prolinamide(hydrobromide salt)

[0399] To a solution ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(195 mg, 0.426 mmol) and Boc-(L)-proline (110 mg, 0.511 mmol) in DMF (6mL) was added diisopropylethylamine (0.22 mL, 1.3 mmol), HOBT (86 mg,0.639 mmol) and EDC (123 mg, 0.639 mmol) and the mixture was allowed tostir at room temperature overnight. Following standard work-upprocedures described above, the crude material was purified by columnchromatography on silica gel (5% methanol in dichloromethane) to give aninseparable mixture of two diastereomeric products (117 mg, 42%).

[0400] Using general procedure D: the intermediate from above wasconverted to the hydrobromide salt with simultaneous deprotection of theBOC group to afford AMD8740 (84 mg). ¹H NMR (D₂O) δ (mixture ofdiastereomers, mixture of rotational isomers) 1.64 (m), 1.90-2.18 (m)total of 16H, 2.44 (m), 2.79 (m) (total of 2H), 2.88 (m, 2H), 2.97 (m,2H), 3.38 (dd, 2H, J=10.2, 7.1 Hz), 3.47 (dd, 2H, J=10.4, 7.2 Hz), 4.37(s), 4.40 (s), 4.43 (s) (total of 6H), 4.60 (m, 4H), 4.99 (m, 2H), 5.51(dd, 1H, J=10.2, 7.1 Hz), 5.81 (dd, 1H, J=10.4, 7.2 Hz), 7.14 (d, 2H,J=8.1 Hz), 7.36 (d, 2H, J=8.1 Hz), 7.45 (d, 2H, J=4.2 Hz), 7.52 (d, 2H,J=1.8 Hz), 7.75 (m, 1H), 7.83 (dd, 1H, J=8.1, 5.3 Hz), 7.96 (m, 2H),8.04 (d, 2H, J=8.1 Hz), 8.21 (m, 1H), 8.24 (m, 1H), 8.34 (dd, 2H, J=4.5,3.9 Hz), 8.49 (t, 2H, J=8.1 Hz), 8.81 (m, 2H); ¹³C NMR (D₂O) δ (bothisomers, mixture of rotational isomers) 20.46, 20.60, 24.47, 24.59,24.94, 24.94, 26.21, 27.60, 27.83, 29.52, 29.93, 46.98, 47.22, 47.79,47.98, 51.60, 55.44, 55.91, 56.64, 59.67, 59.81, 127.81, 128.00, 129.44,129.66, 129.91, 131.00, 131.14, 131.28, 136.22, 136.69, 138.61, 140.54,141.28, 144.70, 144.87, 146.00, 146.05, 146.43, 146.60, 147.91, 148.60,171.23, 172.25, 172.91. ES-MS m/z 456 (M+H). Anal. Calcd. forC₂₈H₃₃N₅O.4.2HBr.1.6H₂O.1.2AcOH: C, 40.74; H, 5.08; N, 7.81; Br 37.44.Found: C, 40.71; H, 5.09; N, 7.36; Br, 37.50.

Example 77 AMD8741: Preparation ofN-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-lysinamide(hydrobromide salt)

[0401] To a solution of N,N′-Di-(t-butoxycarbonyl)-(L)-lysine (1.05 g, 2mmol) in ethyl acetate (15 mL) was added DCC (824 mg, 4.0 mmol) andpentafluorophenol (368 mg, 2.0 mmol). The reaction mixture was stirredat room temperature for 60 minutes then filtered through celite and thefiltrates were concentrated to afford the pentafluorophenol ester inquantitative yield as a white solid. This was used without furtherpurification in the next step.

[0402] To a solution ofN-(t-butyloxycarbonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(125 mg, 0.273 mmol) in dichloroethane (10 mL) was added thepentafluorophenol ester from above (180 mg, 0.355 mmol) and the reactionmixture was heated to 55° C. for 24 hours. The solvents were evaporatedand the residue was purified by column chromatography on silica gel (5%methanol in dichloromethane) to afford a mixture of two inseparablediastereomeric amides (80 mg, 37%).

[0403] Using general procedure D: the intermediate from above wasconverted to the hydrobromide salt with simultaneous deprotection of theBOC groups to afford AMD8741 (66 mg). ¹H NMR (D₂O) δ (mixture ofdiastereomers, mixture of rotational isomers) 1.17-1.83 (m, 20H), 2.01(m, 2H), 2.95-3.08 (m, 8H), 4.38 (s), 4.41 (s), 4.45 (s), total of 4H,4.54 (s, 4H), 4.56 (m, 2H), 5.00 (m, 2H), 5.45 (dd, 1H, J=8.1, 4.3 Hz),5.81 (dd, 1H, J=8.3, 3.6 Hz), 7.20 (d, 2H, J=8.1 Hz), 7.41 (d, 2H J=8.4Hz), 7.50 (m, 4H), 7.75 (m, 6H), 8.20 (m, 2H), 8.31 (m, 1H), 8.37 (d,2H, J=8.1 Hz), 8.37 (d, 1H, J=5.8 Hz), 8.71 (d, 2H, J=8.1 Hz); ¹³C NMR(D₂O) δ (mixture of diastereomers, mixture of rotational isomers) 20.58,21.77, 26.38, 26.74, 27.66, 30.17, 30.75, 39.48, 47.84, 49.50, 49.67,51.16, 52.05, 52.27, 53.20, 55.82, 56.86, 126.08, 126.23, 126.65,128.15, 129.58, 129.80, 130.92, 131.12, 131.33, 136.61, 138.62, 139.37,141.24, 142.25, 147.49, 147.74, 147.85, 148.37, 148.58, 170.63, 172.22.ES-MS m/z 487 (M+H). Anal. Calcd. for C₂₉H₃₈N₆O.5HBr.3H₂O: C, 36.85; H,5.22; N, 8.89; Br 42.29. Found: C, 37.04; H, 5.03; N, 8.76; Br, 42.20.

Example 78 AMD8724: Preparation ofN-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-benzamide(hydrobromide salt)

[0404] To a pre-cooled (ice bath) solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(201 mg, 0.37 mmol) and triethylamine (80 μl, 0.55 mmol) in anhydrousCH₂Cl₂ (4 mL) was added a solution of benzoylchloride (54 μl, 0.46 mmol)in anhydrous CH₂Cl₂ (0.5 mL) and the reaction mixture was allowed tostir at room temperature for 18 hours and then concentrated. The residuewas diluted with ethylacetate (300 mL), washed with sat. aqueous NaHCO₃then brine, dried (Na₂SO₄) and evaporated. The residue was purified bycolumn chromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH₂Cl₂) togive the desired amide (203 mg, 85%) as a yellow oil.

[0405] Using general procedures C and D: the amide (203 mg, 0.31 mmol)was reacted with K₂CO₃ (433 mg, 3.13 mmol) and thiophenol (0.15 mL, 1.46mmol) in DMF (3 mL). Purification of the crude material by radialchromatography on silica gel (1 mm plate, 3:3:94 MeOH/NH₄OH/CH₂Cl₂) gavethe free base (112 mg, 78%) as light yellow oil. Conversion to thehydrobromide salt gave AMD8724 (90 mg). ¹H NMR (CD₃OD) δ 1.64-1.74 (m,2H), 1.97-2.02 (m, 1H), 2.26-2.38 (m, 1H), 2.99 -3.00 (m, 2H), 4.44 (s,2H), 4.63 (s, 2H), 4.93 (overlapped with MeOH, 2H), 5.12-5.24 (m, 1H),7.43-7.45 (m, 2H), 7.52 (d, 4H, J=1.8 Hz), 7.63-7.70 (m, 2H), 7.71-7.73(m, 2H), 7.83-7.90 (m, 1H), 7.95-8.00 (m, 1H), 8.35-8.42 (m, 2H),8.62-8.66 (m, 1H), 8.88-8.90 (b, 1H); ¹³C NMR (CD₃OD) δ 22.41, 28.41,29.26, 52.53, 56.78, 58.07, 67.32, 126.26, 127.69 (b), 128.80, 130.33,130.82, 132.05, 132.47, 132.74, 136.56, 139.83, 140.61, 140.94, 144.53(b), 147.66 (b), 148.43, 149.70 (b), 153.47, 174.09; ES-MS m/z 463.2(M+H); Anal. Calcd. for C₃₀H₃₀N₄O.2.8HBr.2.3H₂O: C, 49.32; H, 5.16; N,7.67; Br, 30.62. Found: C, 49.35; H, 5.06; N, 7.43; Br, 30.53.

Example 79 AMD8725: Preparation ofN-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-picolinamide(hydrobromide salt)

[0406] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(209 mg, 0.39 mmol) in dry DMF (1 mL) was added N-methylmorpholine (0.5mL, 4.45 mmol), picolinic acid (64 mg, 0.52 mmol),1-hydroxybenzotriazole (57 mg, 0.42 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (85 mg, 0.44 mmol). Thereaction mixture was allowed to stir at room temperature for further 18hours and then concentrated. The residue was diluted with ethylacetate(300 mL) and washed with saturated aqueous NaHCO₃, then brine, dried(Na₂SO₄) and evaporated. Purification of the crude material by columnchromatography on silica gel (1.5×20 cm, 50:50 EtOAc/CH₂Cl₂) gave thedesired amide (237 mg, 94%) as a yellow oil.

[0407] Using general procedures C and D: the amide (235 mg, 0.36 mmol)was reacted with K₂CO₃ (300 mg, 2.17 mmol) and thiophenol (0.15 mL, 1.46mmol) in DMF (3 mL). Purification of the crude product by radialchromatography on silica gel (1 mm plate, 3:3:94 MeOH/NH₄OH/CH₂Cl₂) gavethe free base (98 mg, 59%) as a light yellow oil. Conversion of the freebase (98 mg, 0.22 mmol) to the hydrobromide salt gave AMD8725 (90 mg).¹H NMR (CD₃OD) δ 1.79-2.01 (m, 2H), 2.05-2.11 (m, 1H), 2.30-2.41 (m,1H), 3.03 (s, 2H), 4.47 (s, 2H), 4.70 (s, 2H), 4.96 (overlapped withMeOH, 2H), 5.24-5.50 (m, 1H), 7.40-7.42 (m, 1H), 7.54 (d, 2H, J=7.7 Hz),7.64 (d, 2H, J=7.7 Hz), 7.88-7.93 (m, 3H), 8.07-8.13 (m, 1H), 8.23 (b,1H), 8.34-8.47 (m, 3H), 8.66-8.68 (m, 1H), 8.81-8.90 (m, 1H); ¹³C NMR(CD₃OD) δ 22.25, 28.18, 29.17, 52.66, 56.20, 58.64, 126.56, 127.02,128.17, 128.90 (b), 129.93 (b), 130.98, 132.00 (b), 132.58, 132.60,139.45, 140.96, 144.80 (b), 145.10 (b), 145.68 (b), 146.83 (b), 147.57,148.79 (b). ES-MS m/z 464.2 (M+H). Anal. Calcd. forC₂₉H₂₉N₅O.4.0HBr.2.4H₂O: C, 41.94; H, 4.59; N, 8.43; Br, 38.49. Found:C, 41.87; H, 4.58; N, 8.06; Br, 38.61.

Example 80 AMD8713: Preparation ofN′-Benzyl-N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-urea

[0408] To a stirred solution ofN-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-[5,6,7,8-tetrahydro-8-quinolinyl]-1,4-benzenedimethanamine(140 mg, 0.257 mmol) in dichloromethane (5 ml) cooled to 0° C. was addeddropwise, benzyl isocyanate (0.035 mL, 0.284 mmol). The reaction mixturewas then allowed to stir at room temperature for two hours. The mixturewas evaporated and the residue was purified by column chromatography onsilica gel (3% methanol in dichloromethane as eluent) to afford thedesired urea in an 81% yield.

[0409] Using general procedures C and D: the intermediate from above wasreacted with thiophenol and K₂CO₃ in acetonitrile, and the correspondingfree base was converted to the hydrobromide salt to give AMD8713 (61%).¹H NMR (D₂O) δ 1.77 (m, 2H), 1.99 (m, 3H), 2.91 (m, 2H), 4.25 (d, 1H,J=15.3 Hz), 4.34 (d, 1H, J=15.3 Hz), 4.44 (s, 2H), 4.62 (dd, 2H, J=14.8Hz, 8.3 Hz), 4.66 (s, 2H), 5.33 (t, 1H, J=8.3 Hz (NH)), 7.18 (d, 2H,J=6.9 Hz), 7.23 (m, 5H), 7.47 (d, 2H, J=8.1 Hz), 7.77 (dd, 1H, J=8.4,5.3 Hz), 8.11 (m, 2H), 8.26 (d, 1H, J=7.8 Hz), 8.41 (d, 1H, J=5.8 Hz),8.55 (dd, 1H, J=8.1, 5.4 Hz), 8.81 (d, 1H, J=5.3 Hz); ¹³C NMR (D₂O) δ20.83, 20.89, 27.59, 27.73, 44.52, 47.39, 50.79, 51.82, 56.83, 66.46,125.39, 127.57, 127.66, 128.27, 128.56, 129.07, 129.53, 130.95, 139.14,139.26, 139.60, 139.74, 144.14, 145.45, 147.61, 147.73, 151.52, 159.20.ES-MS m/z 492 (M+H). Anal. Calcd. for C₃₁H₃₃N₅O3HBr.3.2H₂O: C, 47.01; H,5.40; N, 8.84; Br, 30.27. Found: C, 46.85; H, 5.22; N, 8.58; Br, 30.50.

Example 81 AMD8712: Preparation ofN′-phenyl-N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-urea

[0410] Using phenyl isocyanate in the above procedure followed bydeprotection and salt formation according to general procedures C and D,afforded AMD8712. ¹H NMR (D₂O) δ 1.79 (m, 1H), 1.99-2.10 (m, 4H), 2.93(m, 2H), 4.46 (s, 2H), 4.70 (s, 2H), 4.80 (m, 2H), 5.44 (br s, 1H (NH)),7.20 (m, 3H), 7.32 (d, 2H, J=7.5 Hz), 7.46 (d, 2H, J=5.7 Hz), 7.54 (d,2H, J=5.1 Hz), 7.79 (dd, 1H, J=8.1, 5.3 Hz), 7.99 (dd, 1H, J=8.1, 8.4Hz), 8.04 (dd, 1H, J=8.4, 5.7 Hz), 8.12 (m, 1H), 8.28 (m, 1H), 8.45 (t,1H, J=8.1 Hz), 8.82 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 20.81, 20.91,27.52, 27.59, 45.22, 50.79, 51.87, 56.75, 66.46, 124.07, 125.50, 125.77,128.23, 128.81, 129.51, 131.06, 137.67, 139.18, 139.43, 139.80, 143.75,145.33, 147.88, 151.07, 158.00. ES-MS m/z 478 (M+H). Anal. Calcd. forC₃₀H₃₁N₅O.3HBr.3.8H₂O: C, 45.68; H, 5.32; N, 8.88; Br, 30.39. Found: C,45.58; H, 5.27; N, 8.64; Br, 30.54.

Example 82 AMD8716: Preparation ofN-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-4-[[(2-pyridinylmethyl)amino]methyl]benzamide(hydrobromide salt)

[0411] A 1 L glass Fisher-Porter bottle was charged with9-amino-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (0.583 g, 3.60mmol), DMF (18 mL), methyl 4-bromobenzoate (0.852 g, 3.96 mmol),dichlorobis(triphenylphosphine)-palladium(II) (0.048 g, 0.07 mmol) andtriethylamine (1.0 mL, 7.17 mmol). Carbon monoxide was bubbled throughthe mixture for 10 minutes. The bottle was capped with a pressure gaugeand the mixture was heated to 80° C. under an atmosphere of carbonmonoxide (45 psi) for 60 hours. The reaction mixture was cooled to roomtemperature, filtered through celite and the cake was washed withCH₂Cl₂. The filtrate was concentrated and the residue was purified bycolumn chromatography on silica gel (100:1 CH₂Cl₂-CH₃OH) to afford 0.198g of the amide-ester as a light yellow oil.

[0412] To a cold (−78° C.), stirred solution of amide-ester from above(0.198 g, 0.61 mmol) in CH₂Cl₂ (5.0 mL) was added DIBAL-H (3.5 mL, 3.5mmol, 1.0 M in CH₂Cl₂). The cooling bath was removed and the reactionmixture was warmed to room temperature. After 2 hours, the mixture wastreated with saturated aqueous sodium/potassium tartrate (40 mL) anddiluted with CH₂Cl₂ (20 mL). The resultant emulsion was vigorouslystirred open to the air until the emulsion became a biphasic mixture.The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (4×20 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. The crude material was purified by column chromatographyon silica gel (20:1 CH₂Cl₂-CH₃OH), to provide 0.120 g of the alcohol asa yellow oil.

[0413] To a stirred solution of the alcohol (0.120 g, 0.43 mmol) in dryTHF (20 mL) was added 2-(N-(2-nitrobenzenesulfonyl)aminomethyl)pyridine(0.185 g, 0.63 mmol) and triphenylphosphine (0.175 g, 0.67 mmol)followed by dropwise addition of diethylazodicarboxylate (0.10 mL, 0.64mmol). The resultant mixture was stirred at room temperature for 3hours. The mixture was concentrated and the residual oil was purified bycolumn chromatography on silica gel (1:1 hexanes-ethyl acetate followedby 50:1 CH₃OH-ethyl acetate) to give 0.235 g of the amide as a yellowsolid.

[0414] Using general procedures C and D: the amide (0.235 g, 0.411 mmol)was recated with thiophenol (0.20 mL, 1.95 mmol) and K₂CO₃ (0.316 g,2.28 mmol) in CH₃CN (8 mL). Purification of the crude material by columnchromatography on silica gel (10:1 CH₂Cl₂-CH₃OH) provided 0.075 g of thefree base of the title compound as a colorless oil. Conversion of thefree base to a hydrobromide salt gave AMD8716 (0.141 g) as an off-whitesolid. ¹H NMR (D₂O) δ 1.44-1.56 (m, 1H), 2.00-2.30 (m, 5H), 3.14-3.17(m, 2H), 4.49 (s, 2H), 4.58 (s, 2H), 5.52 (d, 1H, J=8.1 Hz), 7.65 (d,2H, J=8.4 Hz), 7.72-7.08 (m, 2H), 7.85 (dd, 1H, J=6.0, 7.8 Hz), 7.96 (d,2H, J=8.4 Hz), 8.22 (td, 1H, J=7.8, 1.5 Hz), 8.40 (d, 1H, J=7.8 Hz),8.44 (d, 1H, J=5.4 Hz), 8.71 (d, 1H, J=5.4 Hz); ¹³C NMR (D₂O) δ 25.51,28.52, 31.03, 33.33, 49.49, 51.12, 54.36, 126.07, 126.37, 126.44, 129.09(2 carbons), 130.72 (2 carbons), 134.17, 135.09, 138.06, 142.31, 142.84,147.27, 147.91, 148.14, 155.48, 171.02. ES-MS m/z 387 (M+H). Anal.Calcd. for C₂₄H₂₆N₄O.3.1HBr.2.5H₂O.2.4dioxane: C, 45.15; H, 6.01; N,6.27; Br, 27.71. Found: C, 45.05; H, 6.03; N, 6.29; Br, 27.90.

Example 83 AMD8717: Preparation ofN-(5,6,7,8-tetrahydro-8-quinolinyl)-4-[[(2-pyridinylmethyl)amino]methyl]benzamide(hydrobromide salt)

[0415] In a similar manner to that described above:8-amino-5,6,7,8-tetrahydroquinoline gave AMD8717. ¹H NMR (D₂O) δ1.90-2.16 (m, 3H), 2.20-2.32 (m, 1H), 3.02-3.04 (m, 2H), 4.47 (s, 2H),4.60 (m, 2H), 5.46 (t, 1H, J=6.9 Hz), 7.61 (d, 2H J=8.4 Hz), 7.78-7.87(m, 5H), 8.29 (t, 1H, J=7.8 Hz), 8.37 (d, 1H, J=7.5 Hz), 8.51 (d, 1H,J=5.4 Hz), 8.72 (dt, 1H, J=5.4, 0.9 Hz); ¹³C NMR (D₂O) δ 19.30, 27.54,28.35, 47.78, 49.00, 51.23, 125.87, 126.87, 126.91, 128.75 (2 carbons),130.80 (2 carbons), 134.57, 134.81, 139.77 (2 carbons), 144.00, 146.48,147.46, 148.12, 150.08, 170.42. ES-MS m/z 373 (M+H). Anal. Calcd. forC₂₃H₂₄N₄O.3.0HBr.5.2H₂O.1.2dioxane: C, 40.99; H, 5.82; N, 6.88; Br,29.43. Found: C, 40.97; H, 5.52; N, 6.84; Br, 29.40.

Example 84 AMD8634: Preparation ofN,N′-bis(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0416] 8-amino-5,6,7,8-tetrahydroquinoline (0.169 g, 1.14 mmol) wascondensed with pyridine-2-carboxaldehyde (0.12 mL, 1.26 mmol) inmethanol (6 mL) overnight. Hydrogenation (30 psi, room temperature) ofthe resulting imine over palladium on activated carbon, (10%, 18 mg) for6 hours provided 0.232 g of a brown oil. The oil was dissolved in CH₃CN(20 mL), treated withN-[1-methylene-4-chloromethylenephenylene]-N-(diethylphosphoryl)-2-(aminomethyl)pyridine(0.38 g, 0.99 mmol) and K₂CO₃ (0.358 g, 2,59 mmol) and heated to refluxfor 24 hours. The mixture was cooled to room temperature, concentrated,and partitioned between CH₂Cl₂ (40 mL) and water (20 mL). The phaseswere separated and the aqueous phase was extracted with CH₂Cl₂ (3×20mL). The combined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by column chromatography on basicalumina (20:1 CH₂Cl₂-CH₃OH) provided 0.440 g of a yellow oil.

[0417] Using general procedure D: the diethylphosphoryl group of the oilfrom above was deprotected with HBr/acetic acid to give 0.517 g of a tansolid. The solid was partitioned between CH₂Cl₂ (20 mL) and a 10 Maqueous solution of NaOH (20 mL). The phases were separated and theaqueous phase was extracted with CH₂Cl₂ (4×20 mL). The combined organicextracts were dried (Na₂SO₄) and concentrated. Purification of the crudematerial by radial chromatography on silica gel (2 mm plate, 20:1:1CH₂Cl₂-CH₃OH-NH₄OH) provided the free base of the title compound (0.079g) as a colorless oil. Using general procedure D: the oil was convertedto a hydrobromide salt giving AMD8634 (0.106 g) as a white solid. ¹H NMR(D₂O) δ 1.83-1.86 (m, 1H), 2.17-2.44 (m, 2H); 3.00 (br s, 2H), 3.79 (s,2H), 4.22 (s, 2H), 4.39 (d, 1H, J=16.5 Hz), 4.49 (s, 2H), 4.52 (d, 1H,J=16.5 Hz), 4.64 (dd, 1H, J=10.2, 6.3 Hz), 7.19-7.26 (m, 4H), 7.71-7.78(m, 3H), 7.84 (dd, 1H, J=6, 7.8 Hz), 7.92 (d, 1H, J=8.1 Hz), 8.22 (td,1H, J=7.8, 1.8 Hz), 8.32 (d, 2H, J=8.4 Hz), 8.37 (dd, 1H, J=7.8, 1.5Hz), 8.47 (d, 1H, J=5.4 Hz), 8.64 (d, 1H, J=4.8 Hz), 8.68 (d, 1H, J=5.1Hz); ¹³C NMR (D₂O) δ 20.46, 20.57, 27.90, 49.04, 51.02, 55.65, 55.79,61.92, 125.91, 126.16, 126.47, 126.56, 127.40, 130.13, 130.67 (2carbons), 131.16 (2 carbons), 138.55, 139.61, 140.89, 141.03, 143.26,146.90, 147.33, 147.85, 148.10, 150.92, 153.78. ES-MS m/z 450 (M+H).Anal. Calcd. for C₂₉H₃₁N₅.4.2HBr.1.8H₂O: C, 42.38; H, 4.76; N, 8.52; Br,40.83. Found: C, 42.31; H, 4.79; N, 8.25; Br, 41.03.

Example 85 AMD8774: Preparation ofN,N′-bis(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine(hydrobromide salt)

[0418] 9-Amino-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (0.104 g,0.64 mmol) was condensed with pyridine-2-carboxaldehyde (65 μL, 0.68mmol) in methanol (6 mL) for 2 hours. Hydrogenation (1 atm, roomtemperature) of the resultant imine over palladium on activated carbon,(10%, 38 mg) for 5 hours provided 0.162 g of a yellow oil. The oil wasdissolved in CH₃CN (13 mL), treated withN-[1-methylene-4-chloromethylenephenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(0.263 g, 0.61 mmol) and K₂CO₃ (0.191 g, 1.38 mmol) and heated to refluxfor 24 hours. The mixture was cooled to room temperature, concentrated,and partitioned between CH₂Cl₂ (25 mL) and water (10 mL). The phaseswere separated and the aqueous phase was extracted with CH₂Cl₂ (3×10mL). The combined organic extracts were dried (Na₂SO₄) and concentrated.Purification of the crude material by radial chromatography on silicagel (4 mm plate, 40:1 CH₂Cl₂-CH₃OH containing 1% NH₄OH) provided 0.232 gof a yellow oil.

[0419] Using general procedures C and D: the oil from above was reactedwith thiophenol (0.20 mL, 1.95 mmol) and K₂CO₃ (0.498 g, 3.61 mmol) inCH₃CN (7 mL). Purification of the crude material by radialchromatography on silica gel (2 mm plate, 20:1:1 CH₂Cl₂-CH₃OH-NH₄OH)provided the free base of the title compound (0.136 g) as a yellow oil.Conversion of the free base to a hydrobromide salt gave AMD8774 (0.191g) as a white solid. ¹H NMR (D₂O) δ 1.72-1.92 (m, 4H), 1.98-2.08 (m,1H), 2.18-2.25 (m, 1H), 2.88 (dd, 1H, J=15.3, 5.1 Hz), 3.23-3.31 (m,1H), 3.82 (d, 1H, J=13.5 Hz), 3.92 (d, 1H, J=13.5 Hz), 4.24 (s, 2H),4.32 (d, 1H, J=16.2 Hz), 4.45-4.56 (m, 4H), 7.25 (s, 4H), 7.71-7.81 (m,4H), 7.98 (br d, 1H, J=8.1 Hz), 8.18-8.24 (m, 2H), 8.38 (td, 1H, J=8.1,1.5 Hz), 8.53 (br d, 1H, J=6.0 Hz), 8.60 (dd, 1H, J=6.0, 1.2 Hz), 8.68(br d, 1H, J=5.1 Hz); ¹³C NMR (D₂O) δ 24.68, 24.79, 25.21, 32.09, 49.07,51.06, 54.54, 57.09, 66.14, 126.27, 126.28, 126.47, 126.54, 127.64,130.16, 130.66 (2 carbons), 130.88 (2 carbons), 138.27, 138.77, 141.55,142.93, 143.22, 146.95, 147.18, 147.90, 148.47, 153.73, 154.56. ES-MSm/z 464 (M+H). Anal. Calcd. for C₃₀H₃₃N₅.4.0HBr.2.9H₂O: C, 42.92; H,5.14; N, 8.34; Br, 38.07. Found: C, 42.86; H, 5.14; N, 8.20; Br, 38.17.

Example 86 AMD8775: Preparation ofN,N′-bis(2-pyridinylmethyl)-N′-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1,4-benzenedimethanamine(hydrobromide salt)

[0420] In a similar manner to that described above:7-amino-6,7-dihydro-5H-cyclopenta[b]pyridine andN-[1-methylene-4-chloromethylenephenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridinegave AMD8775 as an orange solid. ¹H NMR (D₂O) δ 2.53-2.64 (m, 2H),3.12-3.20 (m, 1H), 3.26-3.35 (m, 1H), 3.73 (d, 1H, J=12.9 Hz), 3.85 (d,1H, J=12.9 Hz), 4.21 (d, 1H, J=16.8 Hz), 4.24 (s, 2H), 4.39 (d, 1H,J=16.8 Hz), 4.47 (s, 2H), 5.14 (dd, 1H, J=8.4, 7.2 Hz), 7.25 (d, 2H,J=8.1 Hz), 7.30 (d, 2H, J=8.1 Hz), 7.73-7.80 (m, 3H), 7.84 (dd, 1H,J=7.8, 6.0 Hz), 7.91 (d, 1H J=8.1 Hz), 8.24 (td, 1H, J=7.8, 1.5 Hz),8.35 (dd, 1H, J=7.8, 1.5 Hz), 8.40 (d, 1H, J=7.2 Hz), 8.52-8.57 (m, 2H),8.69 (br d, 1H, J=5.1 Hz); ¹³C NMR (D₂O) δ 22.49, 28.77, 48.91, 51.13,54.64, 55.89, 67.47, 126.19, 126.64 (2 carbons), 126.85, 127.22, 130.06,130.67 (2 carbons), 130.96 (2 carbons), 138.85, 139.82, 140.93, 143.58,144.46, 144.96, 146.70, 147.32, 147.69, 154.19, 156.49. ES-MS m/z 436(M+H). Anal. Calcd. for C₂₈H₂₉N₅.4.0HBr.2.7H₂O: C, 41.63; H, 4.79; N,8.67; Br, 39.56. Found: C, 41.59; H, 4.72; N, 8.43; Br, 39.59.

Example 87 AMD8819: Preparation ofN,N′-bis(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0421] In a similar manner to that described above:1-amino-1,2,3,4-tetrahydronapthalene andN-[1-methylene-4-chloromethylenephenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridinegave AMD8819 as a white solid. ¹H NMR (D₂O) δ 1.62-1.68 (m, 1H),2.05-2.19 (m, 2H), 2.39-2.44 (m, 1H), 2.69-2.81 (m, 2H), 4.30-4.84 (m,6H), 4.52 (s, 2H), 4.76-4.79 (m, 1H, overlaps with HOD), 7.16-7.26 (m,3H), 7.37-7.50 (m, 6H), 7.67 (dd, 1H, J=6.0, 3.3 Hz), 7.79-7.93 (m, 3H),8.32 (td, 1H, J=7.8, 1.5 Hz), 8.47 (dd, 1H, J=5.7, 1.5 Hz), 8.71 (br d,1H J=5.7 Hz); ¹³C NMR (D₂O) δ 21.01, 22.84, 29.19, 48.12, 51.37, 53.29,56.11, 62.74, 125.36, 125.47, 127.17, 127.47, 127.63, 128.58, 129.27,130.28, 131.03 (2 carbons), 131.32, 131.49, 131.58 (2 carbons), 134.17,141.15, 142.17, 145.29, 145.66, 145.86, 146.47, 150.58. ES-MS m/z 449(M+H). Anal. Calcd. for C₃₀H₃₂N₄.4.0HBr.2.0H₂O: C, 44.58; H, 4.99; N,6.93; Br, 39.54. Found: C, 44.82; H, 5.02; N, 6.86; Br, 39.30.

Example 88 AMD8768: Preparation ofN,N′-bis(2-pyridinylmethyl)-N′-[(5,6,7,8-tetrahydro-8-quinolinyl)methyl]-1,4-benzenedimethanamine(hydrobromide salt)

[0422] 8-carboxymethyl-5,6,7,8-tetrahydroquinoline

[0423] To a cold (−78° C.), stirred solution of5,6,7,8-tetrahydroquinoline (0.713 g, 5.35 mmol) in dry THF (50 mL) wasadded tert-butyllithium (1.7 M in pentane, 4.5 mL, 7.65 mmol). Theinitially colorless solution turned deep red. After one hour, CO₂ gaswas bubbled through the reaction mixture for 15 minutes. The red colorfaded and the solution became cloudy and colorless. The reaction mixturewas warmed to room temperature, treated with water (30 mL), and dilutedwith diethyl ether (30 mL). The phases were separated and the aqueousphase was extracted with ether (3×30 mL). The aqueous phase wasconcentrated under reduced pressure to provide a white solid. Methanol(50 mL) was added to the solid followed by the dropwise addition ofconcentrated H₂SO₄ (˜1 mL) until the mixture became homogenous. Theresultant solution was heated to reflux overnight and then was cooled toroom temperature. The solution was concentrated and the residue wasdissolved in saturated aqueous Na₂CO₃ (30 mL) and CH₂Cl₂ (30 mL). Thephases were separated and the aqueous phase was extracted with CH₂Cl₂(3×30 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification of the crude material by radialchromatography on silica gel (4 mm plate, 20:1 CH₂Cl₂-CH₃OH) provided8-carbomethoxy-5,6,7,8-tetrahydroquinoline (0.724 g, 72%) as a paleyellow oil. ¹H NMR (CDCl₃) δ 1.72-1.82 (m, 1H), 1.92-2.03 (m, 1H),2.12-2.24 (m, 2H), 2.71-2.91 (m, 2H), 3.74 (s, 3H), 3.98 (dd, 1H, J=6.6,6.6 Hz), 7.09 (dd, 1H, J=7.8, 4.8 Hz), 7.40 (dd, 1H, J=7.5, 0.9 Hz),8.40 (d, 1H, J=4.8 Hz); ¹³C NMR (CDCl₃) δ 20.68, 27.31, 28.70, 48.55,52.40, 122.39, 132.83, 137.48, 147.60, 154.13, 175.13. ES-MS m/z192(M+H).

[0424] 8-hydroxymethyl-5,6,7,8-tetrahydroquinoline

[0425] To a cold (−78° C.), stirred solution of8-carboxymethyl-5,6,7,8-tetrahydroquinoline (0.820 g, 4.29 mmol) inCH₂Cl₂ (21 mL, 0.2M) was added DIBAL-H (15.0 mL, 15.0 mmol, 1.0 M inCH₂Cl₂) over. 10 minutes. The cooling bath was removed and the reactionmixture was warmed to room temperature. After 3.5 hours, the mixture wastreated with saturated aqueous sodium/potassium tartrate (100 mL) anddiluted with CH₂Cl₂ (21 mL). The resultant emulsion was vigorouslystirred open to the air until the emulsion became a biphasic mixture.The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (4×25 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. The crude material was purified by radial chromatographyon silica gel (4 mm plate, 20:1 CH₂Cl₂-CH₃OH), to provide8-hydroxymethyl-5,6,7,8-tetrahydroquinoline (0.573 g) as a yellow oil.

[0426] 8-(aminomethyl)-5,6,7,8-tetrahydroquinoline

[0427] To a stirred solution of8-hydroxymethyl-5,6,7,8-tetrahydroquinoline (0.573 g, 3.51 mmol) in dryTHF (35 mL) was added phthalimide (0.795 g, 5.40 mmol) andtriphenylphosphine (1.452 g, 5.53 mmol) followed by the dropwiseaddition of diethylazodicarboxylate (0.90 mL, 5.72 mmol). The resultantmixture was stirred at room temperature overnight. The mixture wasconcentrated and filtered (2:1 hexanes-ethyl acetate) through a shortpad of silica gel (50 g). The appropriate fractions were combined andconcentrated. Purification of the residual oil by radial chromatographyon silica gel (4 mm plate, 3:1 hexanes-ethyl acetate) provided 0.711 gof a yellow semi-solid. The yellow semi-solid was dissolved in ethanol(25 mL), treated with hydrazine (1.2 mL, 24.7 mmol), and stirred at roomtemperature overnight. A voluminous, white precipitate formed. Thereaction mixture was diluted with ether, filtered, and the filtratesconcentrated to provide a yellow oil. Purification of the crude materialby column chromatography on silica gel (20:1:1 CH₂Cl₂-CH₃OH-NH₄OH)provided 0.217 g of 8-(aminomethyl)-5,6,7,8-tetrahydroquinoline as ayellow oil. ¹H NMR (CDCl₃) δ 1.59-2.01 (m, 6H), 2.73 (t, 2H, J=5.4 Hz),2.82-2.29 (m, 1H), 2.99 (dd, 1H, J=12.6, 6.6 Hz), 3.11 (dd, 1H, J=12.6,5.4 Hz), 7.00 (dd, 1H, J=7.2, 4.8 Hz), 7.32 (d, 1H, J=7.2 Hz), 8.36 (d,1H, J=4.8 Hz).

[0428] Preparation of AMD8768.

[0429] 8-(aminomethyl)-5,6,7,8-tetrahydroquinoline (0.283 g, 1.74 mmol)was condensed with pyridine-2-carboxaldehyde (0.19 mL, 2.00 mmol) inmethanol (17 mL) overnight. Hydrogenation (1 atm, room temperature) ofthe resulting imine over palladium on activated carbon, (10%, 54 mg) for5 hours provided 0.452 g of a yellow oil. The oil was dissolved in CH₃CN(35 mL), treated withN-[1-methylene-4-chloromethylenephenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(0.8168 g, 1.89 mmol) and K₂CO₃ (0.546 g, 3.95 mmol) and heated toreflux for 24 hours. The mixture was cooled to room temperature,concentrated, and partitioned between CH₂Cl₂ (40 mL) and water (20 mL).The phases were separated and the aqueous phase was extracted withCH₂Cl₂ (3×20 mL). The combined organic extracts were dried (Na₂SO₄) andconcentrated. Purification of the crude material by columnchromatography on silica gel (10:1 CH₂Cl₂-CH₃OH) provided 0.90 g of ayellow solid.

[0430] Using general procedures C and D: the yellow solid from above(0.90 g, 1.39 mmol) was reacted with thiophenol (0.85 mL, 8.28 mmol) andK₂CO₃ (1.949 g, 14.10 mmol) in CH₃CN (25 mL). Purification of the crudematerial by radial chromatography on silica gel (4 mm plate, 20:1:1CH₂Cl₂-CH₃OH-NH₄OH) provided the free base of the title compound (0.67g) as a yellow oil. Conversion of the free base to a hydrobromide saltgave AMD8768 (0.89 g) as a white solid. ¹H NMR (D₂O) δ 1.55-1.60 (m,1H), 1.70-1.77 (m, 1H), 1.93-1.98 (m, 1H), 2.05-2.11 (m, 1H), 2.81-2.85(m, 2H), 2.95-3.09 (m, 2H), 3.49-3.57 (m, 1H), 3.86 (d, 1H, J=13.2 Hz),3.98 (d, 1H, J=13.2 Hz), 4.31 (d, 2H, J=5.1 Hz), 4.38 (s, 2H), 4.62 (s,2H), 7.42 (s, 4H), 7.72 (dd, 1H, J=8.1, 6.0 Hz), 7.85-8.04 (m, 4H), 8.18(br d, 1H, J=8.1 Hz), 8.42-8.48 (m, 3H), 8.64 (dd, 1H, J=5.7, 0.9 Hz),8.78 (br d, 1H, J=5.7 Hz); ¹³C NMR (D₂O) δ 17.61, 24.02, 27.39, 34.64,48.06, 51.54, 56.11, 58.04, 58.94, 124.84, 126.43, 127.54, 127.73,127.88, 136.08, 130.81 (2 carbons), 131.19 (2 carbons), 138.42, 138.93,139.12, 142.10, 145.19, 145.85, 146.42, 146.91, 147.41, 153.19, 153.37.ES-MS m/z 464 (M+H). Anal. Calcd. for C₃₀H₃₃N₅.4.7HBr.3.2H₂O: C, 39.97;H, 4.93; N, 7.77; Br, 41.66. Found: C, 40.04; H, 4.98; N, 7.63; Br,41.69.

Example 89 AMD8767: Preparation ofN,N′-bis(2-pyridinylmethyl)-N′[(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)methyl]-1,4-benzenedimethanamine(hydrobromide salt)

[0431] Using similar procedures to those described above:Cyclopentenopyridine gave7-(aminomethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine. ¹H NMR (CDCl₃) δ1.50 (br s, 2H, NH₂ ), 1.81-1.93 (m, 1H), 2.26-2.38 (m, 1H), 2.82-3.12(m, 4H), 3.22 (quintet, 1H, J=7.2 Hz), 7.04 (dd, 1H, J=7.2, 4.8 Hz),7.49 (d, 1H, J=7.2 Hz), 8.36 (d, 1H, J=4.8 Hz).

[0432] Reaction of 7-(aminomethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine,pyridine-2 carboxaldehyde andN-[1-methylene-4-chloromethylenephenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridineusing similar procedures to those described above gave AMD8767 as awhite solid. ¹H NMR (D₂O) δ 2.14-2.22 (m, 1H), 2.50-2.59 (m, 1H),2.99-3.07 (m, 3H), 3.25 (dd, 1H, J=13.2, 6.0 Hz), 3.89-3.99 (m, 2H),4.04 (d, 1H, J=9.9 Hz), 4.32 (d, 2H, J=3 Hz), 4.34 (s, 2H), 4.58 (s,2H), 7.37-7.44 (m, 4H), 7.72-7.81 (m, 2H), 7.82-7.94 (m, 3H), 8.28-8.44(m, 4H), 8.61 (dd, 1H, J=5.1, 1.2 Hz), 8.75 (dd, 1H, J=5.1, 1.2 Hz); ¹³CNMR (D₂O) δ 33.64,33.82, 46.86, 53.12, 56.25, 61.12, 62.10, 63.99,130.47, 131.02, 132.10, 132.25, 132.27, 135.06, 135.57 (2 carbons),136.06 (2 carbons), 142.65, 143.27, 147.36, 148.13,149.85,150.01,150.44, 151.01,151.61, 158.11, 164.21; ES-MS m/z 450(M+H). Anal. Calcd. for C₂₉H₃₁N₅.4.7HBr.3.3H₂O: C, 39.17; H, 4.79; N,7.87; Br, 42.23. Found: C, 39.07; H, 4.58; N, 7.66; Br, 42.46.

Example 90 AMD8838: Preparation ofN-(2-pyridinylmethyl)-N-(2-methoxyethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0433] To a stirred solution ofN-(diethoxyphosphoryl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(328 mg, 0.66 mmol) in dry CH₂Cl₂ (5 mL) was added methoxyacetic acid(0.15 mL, 1.95 mmol), N,N-diisopropylethylamine (0.35 mL, 2.01 mmol),1-hydroxybenzotriazole hydrate (135 mg, 1.00 mmol) and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (191 mg, 1.00mmol) and the mixture was stirred at room temperature for 18 h. Thereaction mixture was partitioned between CH₂Cl₂ (20 mL) and saturatedaqueous sodium bicarbonate (30 mL) and the organic phase dried (MgSO₄),filtered and evaporated in vacuo. Purification by column chromatographyon silica gel (CH₂Cl₂/MeOH, 95:5) gave the intermediate amide (345 mg,92%) as a pale yellow foam.

[0434] To a stirred solution of the amide from above (345 mg, 0.61 mmol)in dry toluene (5 mL) was added a 70% w/w solution of sodiumbis(2-methoxyethoxy)aluminium hydride in toluene (0.59 mL, 2.04 mmol)and the mixture stirred for 40 min. The reaction mixture was quenchedwith 1 N HCl (5 mL) and stirred for 30 min. The mixture was partitionedbetween 1 N NaOH (25 mL) and CH₂Cl₂ (25 mL) and the aqueous layer washedwith CH₂Cl₂ (2×15 mL). The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. Purification of the crude product bycolumn chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 95:5:0 followedby 95:4:1) afforded the reduced tertiary amine (166 mg, 49%) as a clearoil.

[0435] To a stirred solution of the tertiary amine (116 mg, 0.21 mmol)in glacial acetic acid (1 mL) was added an HBr saturated solution ofacetic acid (1 mL) and the mixture was stirred at room temperature for17 h. Diethyl ether (20 mL) was added resulting in the formation of awhite precipitate. The solid was allowed to settle to the bottom of theflask and the supernatant solution was decanted off. The solid waswashed by decantation with ether (4×10 mL) and the remaining traces ofsolvent removed by evaporation under reduced pressure. The HBr salt wasthen re-dissolved in MeOH (1 mL) and partitioned between CH₂Cl₂ (25 mL)and 1 N NaOH (30 mL). The aqueous phase was washed with CH₂Cl₂ (2×15 mL)and the combined organic layers dried (Na₂SO₄), filtered andconcentrated in vacuo to give the crude free amine as a brown oil.Purification of the crude amine by column chromatography on silica gel(CH₂Cl₂/MeOH, 92:8) gave the free base of the title compound as acolorless oil. Using general procedure D: Conversion of the free base(23 mg, 0.042 mmol) to a hydrobromide salt followed by re-precipitationof the crude material from methanol/ether gave AMD8838 as a white solid(39 mg, quantitative). ¹H NMR (D₂O) δ 1.79-1.83 (br m, 1H), 2.04-2.19(m, 2H), 2.44-2.48 (m, 1H), 2.86-2.89 (m, 2H), 3.17 (s, 3H), 3.32-3.49(m, 2H), 3.52-3.57 (m, 1H), 3.77 (td, 1H, J=8.7, 3.0 Hz), 4.21 (d, 1H,J=13.2 Hz), 4.34 (d, 1H, J=13.5 Hz), 4.40 (s, 2H), 4.55 (s, 2H),4.71-4.73 (m, 1H), 7.44 (dd, 1H, J=8.0, 5.0 Hz), 7.55 (br s, 4H),7.73-7.81 (m, 3H), 8.24 (td, 1H, J=8.0, 2.0 Hz), 8.49 (d, 1H, J=5.0 Hz),8.70 (d, 1H, J=5.0 Hz); ¹³C NMR (D₂O) δ 20.37, 20.79, 27.36, 49.04,50.22, 51.24, 54.81, 58.59, 61.95, 66.63, 124.96, 126.67 (2 carbons),131.29 (4 carbons), 131.96, 133.67, 136.52, 140.97, 143.58, 145.61,146.70, 147.73, 149.14. ES-MS m/z 417 (M+H). Anal. Calcd. forC₂₆H₃₂N₄O.4.0HBr.2.2H₂O: C, 40.04; H, 5.22; N, 7.18; Br, 40.98. Found:C, 40.11; H, 5.28; N, 7.08; Br, 40.96.

Example 91 AMD8871: Preparation ofN-(2-pyridinylmethyl)-N-[2-(4-methoxyphenyl)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt)

[0436] To a solution ofN-(diethoxyphosphoryl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(641 mg, 1.30 mmol) and 4-methoxyphenylacetic acid (646 mg, 3.89 mmol)in CH₂Cl₂ (20 mL) was added N,N-diisopropylethylamine (0.45 mL, 2.59mmol), 1-hydroxybenzotriazole hydrate (265 mg, 1.96 mmol) and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (EDC) (360 mg, 1.88mmol) and the mixture was stirred at room temperature for 17 hours.Purification of the crude product by column chromatography on silica gel(CH₂Cl₂/MeOH, 96:4) gave the desired amide (688 mg, 77%) as a yellowfoam. Using general procedure D: the diethoxyphosphoryl group wasremoved with HBr/acetic acid to give the amino-amide (591 mg, 78%) as ayellow foam.

[0437] To a stirred solution of the amine (591 mg, 1.17 mmol) in dryCH₃CN (5 mL) was added allyl bromide (0.16 mL, 1.9 mmol) and powderedpotassium carbonate (378 mg, 2.74 mmol) and the mixture was stirred for2 h. The reaction was diluted with CH₂Cl₂ (25 mL) and water (25 mL) andthe aqueous layer washed with CH₂Cl₂ (2×15 mL). The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo.Purification of the crude product by column chromatography on silica gel(CH₂Cl₂/MeOH, 96:4) afforded the N-allyl-protected amide (600 mg, 94%)as an orange foam.

[0438] To a solution of the N-allyl amide (600 mg, 1.10 mmol) in drytoluene (5 mL) was added a 70% w/w solution of sodiumbis(2-methoxyethoxy)aluminum hydride in toluene (0.95 mL, 3.29 mmol) andthe mixture stirred for 4.5 h. Purification of the crude product bycolumn chromatography on silica gel (CH₂Cl₂/MeOH, 95:5 to 9:1) affordedthe tertiary amine (222 mg, 38%) as a pale yellow oil.

[0439] To a stirred solution of the N-allyl-protected amine in dryCH₂Cl₂ (5 mL) (150 mg, 0.28 mmol) was addedtetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) andN,N′-dimethylbarbituric acid (132 mg, 0.85 mmol) and the mixture stirredfor 20 hours. The reaction was diluted with CH₂Cl₂ (20 mL) and saturatedaqueous sodium bicarbonate (20 mL) and the aqueous layer washed withCH₂Cl₂ (2×15 mL). The combined organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. Purification of the crude product bycolumn chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 95:5:0 followedby 94:5:1) afforded the free base of the title compound (44 mg, 32%) asan orange oil. Using general procedure D: the free base (44 mg, 0.089mmol) was converted to a hydrobromide salt. Re-precipitation of thecrude material from methanol/ether gave AMD8871 (69 mg, 91%) as a beigesolid. ¹H NMR (D₂O) δ 1.80-1.84 (br m, 1H), 2.00-2.19 (m, 2H), 2.47-2.50(br m, 1H), 2.83-2.94 (br m, 4H), 3.29-3.34 (m, 1H), 3.66-3.69 (br m,1H), 3.80 (s, 3H), 4.15-4.18 (m, 1H), 4.39 (d, 1H, J=13.2 Hz), 4.45 (d,1H, J=13.2 Hz), 4.60 (s, 2H), 4.79 (s, 2H, overlap with HOD), 6.81 (d,2H, J=8.0 Hz), 6.97 (d, 2H, J=8.0 Hz), 7.32-7.35 (br m, 3H), 7.44-7.46(br m, 2H), 7.68 (d, 1H, J=8.0 Hz), 7.84-7.96 (m, 2H), 8.32-8.40 (br m,2H), 8.75 (br s, 1H); ¹³C NMR (D₂O) δ 20.41, 20.98, 27.19, 30.26, 48.31,51.38, 52.16, 54.61, 55.91, 62.38, 114.98 (2 carbons), 124.78, 127.38,127.54, 128.08, 130.81 (2 carbons), 131.35 (4 carbons), 131.93, 132.20,135.60, 139.69, 145.39, 145.50, 146.60, 146.63, 148.28, 158.59. ES-MSm/z 493 (M+H). Anal. Calcd. for C₃₂H₃₆N₄O.3.9HBr.1.6H₂O: C, 45.92; H,5.19; N, 6.69; Br, 37.23. Found: C, 46.13; H, 5.04; N, 6.57; Br, 36.90.

Example 92 AMD8844: Preparation ofN,N′-bis(2-pyridinylmethyl)-1,4-(5,6,7,8-tetrahydro-8-quinolinyl)benzenedimethanamine(hydrobromide salt)

[0440] To a solution ofN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(t-butoxycarbonyl)-2-(aminomethyl)pyridine(1.25 g, 3.8 mmol) in methanol (50 mL) was added 2-aminomethylpyridine(0.400 mL, 3.8 mmol). The reaction mixture was stirred at roomtemperature for 3 hours and then evaporated to afford the correspondingimine in quantitative yield. ¹H NMR (CDCl₃) δ: 1.44 (s, 9H), 4.47 (m,2H), 4.60 (m, 2H), 7.15 (m, 1H), 7.40 (m, 2H), 7.61 (dd, 1H, J=7.1, 6.8Hz), 7.80 (d, 2H, J=7.1 Hz), 8.50 (d, 1H, J=4.8 Hz), 9.98 (s, 1H).

[0441] To a cooled (0° C.) solution of 5,6,7,8-tetrahydroquinoline (266mg, 2.0 mmol) in THF (20 mL) was added nBuLi (1.5 mL of a 1.5M solutionin hexanes, 2.5 mmol) over 5 minutes. The resulting bright crimsonsolution was then stirred at 0° C. for one hour, then a freshly preparedsolution of anhydrous cerium trichloride in THF (8 mL of a 0.25Msolution, 2 mmol) was added over ten minutes. The solution was stirredat 0° C. for a further 60 minutes, during which time, the reactionturned a brick red colour. A solution of the imine (832 mg, 2.0 mmol) inTHF (3 mL) was then added over 10 minutes. The resulting deep violetsolution was stirred at 0° C. for three hours. Saturated aqueousammonium chloride was then added, and the mixture was extractedrepeatedly with dichloromethane. The combined organic extracts weredried, filtered and evaporated and the residue was purified by columnchromatography on silica gel (5% MeOH in CH₂Cl₂) to afford the desiredproduct (518 mg, 44%).

[0442] Using general procedure D: the intermediate from above wasconverted to a hydrobromide salt with simultaneous deprotection of theBOC group to afford AMD8844 (81 mg). ¹H NMR (D₂O) δ: 1.44 (m, 4H), 2.77(m, 2H), 3.67 (m, 1H), 4.11 (dq, 2H, J=15.0, 3.1 Hz), 4.26 (m, 1H), 4.44(s, 2H), 4.73 (s, 2H), 7.41 (d, 2H, J=7.2 Hz), 7.50 (d, 2H, J=7.2 Hz),7.65 (t, 1H, J=6.6 Hz), 7.83 (m, 2H), 8.06 (t, 1H, J=6.8 Hz), 8.19 (m,2H), 8.40 (t, 1H, J=7.8 Hz), 8.59 (m, 3H), 8.81 (d, 1H, J=5.8 Hz); ¹³CNMR (D₂O) δ 19.20, 24.73, 27.57, 65.76, 125.18, 126.85, 128.06, 128.43,128.95, 129.26, 130.83, 131.46, 138.90, 139.12, 139.61, 142.01, 143.76,145.08, 147.39, 148.06, 151.65, 152.45. ES-MS m/z 450 (M+H). Anal.Calcd. for C₂₉H₃₁N₅.4.7HBr.3.0 H₂O: C, 39.41; H, 4.75; N, 7.92; Br,42.49. Found: C, 39.64; H, 4.65; N, 7.59; Br, 42.29.

Example 93

[0443] Methods for parallel solution phase combinatorial synthesis ofanalogs from the following intermediates:

[0444]N-(2-nitrobenzenesulfonyl)-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine.

[0445]N-(2-nitrobenzenesulfonyl)-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine.

[0446]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-[2-(2-pyridinyl)ethyl]-1,4-benzenedimethanamine.

[0447]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-[2-(2-pyridinyl)ethyl]-1,3-benzenedimethanamine.

[0448] Target compounds were prepared by parallel solution phasecombinatorial synthesis via a two-step procedure. (a) Reaction of theintermediate amines from above (0.45 mmol scale) with commerciallyavailable aldehydes and ketones and sodium cyanoborohydride in methanol;(b) deprotection of the 2-nitrobenzenesulfonyl group by reaction of theintermediate from step (a) with thiophenol and DBU in DMF; (c)purification.

[0449] Step (a): Reductive Amination Procedure (0.45 mmol).

[0450] Reaction: 0.5 mmol (1.11 eq.) of aldehyde or ketone was weighedinto a 20 mL scintillation vial containing a small amount of activatedmolecular sieve. 0.5 mL of 0.9M solution (1.0 eq.) of intermediate amine(in MeOH) was added, followed by 1 mL of a 0.6M solution of sodiumcyanoborohydride in MeOH (1.33 eq.). The reaction was then diluted to 4mL with MeOH. Finally, 0.5 mL of 1M acetic acid (in MeOH) was added. Thereaction mixture was shaken (on an orbital shaker) for 48 hours.

[0451] Work-up: 0.5 mL of 1M sodium borohydride (in MeOH) was added toconvert any unreacted carbonyl to the corresponding alcohol. After 15min., the reaction was quenched with 4 mL of 2N HCl. The reactionmixture was shaken in a fume hood for 15 minutes. 2 mL of 7N NaOH wasthen added, followed by 5 mL of methylene chloride. After shaking for 20minutes the organic layer was separated and evaporated (ambienttemperature vacuum centrifuge for 4 hours).

[0452] Alternative Reductive Amination Procedure.

[0453] This procedure was used with all aldehydes that incorporated apyrrole, indole, benzimidazole or imidazole functionality (0.45 mmolscale).

[0454] Reaction: 0.9 mmol (2.0 eq.) of aldehyde was weighed into a 20 mLscintillation vial containing a small amount of activated molecularsieve. 0.5 mL of 0.9M solution (1.0 eq.) of the intermediate amine (intrimethylorthoformate) was added. A further 2.5 mL oftriethylorthoformate was added and the mixture was stirred for 30 min.Solid sodium cyanoborohydride was then added (2.25 mmol, 5 eq.) followedby 0.05 mL of acetic acid, and the mixture was shaken for 48 hours.

[0455] Work-up: 0.5 mL of 1M sodium borohydride (in MeOH) was added toconvert any unreacted carbonyl compound to the corresponding alcohol.After 30 minutes the reaction was quenched by slow addition of 2N HCl (3mL). The reaction mixture was shaken in a fume hood for 15 minutes. 2 mLof 7N NaOH was added followed by 5 mL of methylene chloride. Aftershaking for 20 minutes the organic layer was separated and evaporated(ambient temperature vacuum centrifuge for 4 hours).

[0456] The reaction products were deprotected without furtherpurification.

[0457] Step B: Deprotection of the 2-nitrobenzenesulfonyl Group

[0458] Reaction: 1.5 mmol (3.33 eq.) of DBU and 0.75 mmol (1.67 eq.) ofthiophenol were dissolved in 2.5 mL DMF were added to each crudereaction product and stirred at room temperature for 14 hours.

[0459] Work-up: 2 mL of water and 2 mL of methylene chloride were addedto the mixture and shaken for 20 minutes. The organic layer wasseparated into 4 equal parts in 1 dram vials and evaporated (ambienttemperature vacuum centrifuge for 20 hours).

[0460] Two methods were used to purify the samples:

[0461] Step C: Purification by Parallel Preparative HPLC.

[0462] 3 of the four 1 dram vials for each sample were purified byhigh-throughput preparative HPLC parallel purification process using aBiotage Parallex instrument. The crude, de-protected material wasdissolved in 1 mL of a mixture of 65:35 DMF/water.

[0463] The 1 mL solution was loaded into the injection loop of the HPLCwhich already contained starting eluent (water/acetonitrile, 90/10). A100×20 mm YMC C18 120 A column was used and fractions were collected bymonitoring at 254 and 307 nm. A gradient of 90/10 H₂O/CH₃CN to 100%CH₃CN over 8 minutes at a flow rate of 35 mL/minute was used. Each runwas followed by a 3 minute equilabration/wash with 50/50 H₂O/CH₃CN. Eachfraction was analyzed by ES FI-MS for the target compound, and thepurity of fractions containing the desired products were determined byLC-MS.

[0464] Step C: Purification by Traditional Preparative HPLC.

[0465] One vial each of the crude products were purified on a Waters 600Delta Prep instrument. The crude de-protected material was dissolved in80:20 methylene chloride/MeOH at a concentration of ca. 75 mg/100 μL.The 100 μL sample was injected onto a 100×20 mm YMC C18 120A column, andfractions were collected by UV monitoring at 254 nm and a 8% thresholdtrigger. Flow rate 10 mL/min; gradient of 80/20 H₂O/CH₃CN to 100% CH₃CNover 20 minutes, isocratic at 100% CH₃CN from 20-30 min, then back to80/20 from 30-36 minutes. Each fraction was analyzed by ES FI-MS and %purity of fractions containing desired product was further determined byLC-MS.

[0466] Products exhibiting a sample purity of greater then 90% by LC-MSwere considered suitable for testing.

Example 94

[0467] Methods for parallel solution phase combinatorial synthesis ofanalogs from the following intermediates:

[0468]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine.

[0469]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine.

[0470]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine.

[0471]N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,3-benzenedimethanamine.

[0472] Target compounds were prepared by parallel solution phasecombinatorial synthesis via a two-step procedure. (a) Reaction of theintermediate amines from above (0.5 mmol scale) with commerciallyavailable aldehydes and ketones and sodium cyanoborohydride in methanolwith a catalytic volume of acetic acid; (b) deprotection of the2-nitrobenzenesulfonyl group by reaction of the intermediate from step(a) with thiophenol and K₂CO₃ in acetonitrile.

[0473] Step A:

[0474] Reaction: To the pre-weighed amine intermediate from above (0.5mmol) and the aldehyde or ketone (1.5 equiv.) was added MeOH (5 mL),acetic acid (0.1 mL) and molecular sieves and the reaction vial wasshaken for 12 hours. Sodium cyanoborohydride (1.5 equiv.) was then addedand the reaction vial was shaken for 96 hours.

[0475] Work-up: To the vial is added, 2N NaOH (2 mL) and the solution isextracted with CH₂Cl₂ (3×5 mL) with shaking for 30 mins and separationof the organic phases, followed by evaporation of the solvent underreduced pressure (speed vac).

[0476] Step B:

[0477] The intermediate from above is reacted with thiophenol (5.0equiv.) and powdered potassium carbonate (8.0 equiv.) in acetonitrile(10 mL) with shaking for 4 hours. The solvent was removed by evaporationunder reduced pressure (Savant Speed Vac Plus: SC210A) for 12 hours atroom temperature. Dichloromethane (5 mL) and water (5 mL) were thenadded to the residue, the phases were separated, and the aqueous layerwas extracted with CH₂Cl₂ (2×5 mL). The combined organic phases werewashed with brine (5 mL) and evaporated under reduced pressure (SavantSpeed Vac Plus) for 24 hours at room temperature.

[0478] The crude reaction products were analyzed by HPLC with multiplepost-column detection: positive mode electrospray MS (API 150MCA), UV at254 nm and evaporative light scattering (ELS). Chromatography conditionswere as follows: Column: Monitor C8, 30×4.6 mm id; flow rate 1200μL/min.; Solvent A: H₂O w/5 mM NH₄OAc and Solvent B: acetonitrile with 5mM NH₄OAc. Gradient (A/B): 90/10 (t=0), 10/90 (t=8 min), 10/90 (t=9.5min), 90/10 (t=10.25 min), 90/10 (t=11 min).

[0479] Compounds exhibiting a molecular ion (MS) for the desired targetcompound and an ELS purity of greater than 90% were plated for testing.Compounds exhibiting an ELS purity of less than 90% were purified bypreparative HPLC using either of the two following conditions:Preparative HPLC Purification: Condition 1 Solvent A H₂O/NH₄OAc SolventB CH₃CN Wash 50:50 MeOH/CH₃CN UV1 307 nm UV2 254 nm Inj. Loop Vol. 2 mLInj. Vol. 1 mL Column 250 × 20 mm id; C18 Step Starting Ending DurationFlow No. Action B % B % (min) Rate 1 Equilibration 15 15 0.30 30 mL/min2 Injection 10 10 0.27 30 mL/min 3 Gradient 10 100 5.30 35 mL/min 4Gradient 100 100 1.30 35 mL/min 5 Gradient 100 10 0.10 35 mL/min 6Gradient 10 10 2.00 35 mL/min

[0480] Preparative HPLC Purification: Condition 2 Solvent A H₂O SolventB CH₃CN UV1 254 nm UV2 219 nm Inj. Loop Vol. 2 mL Inj. Vol. 1 mL Column100 × 20 mm id; C18, 120A Time A% B% Flow Rate 0 90 10 20 mL/min 21 0100 20 mL/min 24 0 100 20 mL/min

[0481] Peaks corresponding to the molecular ion of the desired compoundwere collected and evaporated under reduced pressure (Speed Vac) andweighed.

[0482] The following compounds (Examples 95-191) were prepared by theprocedures described in working Examples 93 and 94. A summary ofstructures and observed molecular ions (LC-MS analysis) for Examples95-191 are shown in Table 2.

Example 95 AMD7129:N-[(2,3-dimethoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 96 AMD7130:N,N′-bis(2-pyridinylmethyl)-N-[1-(N″-phenyl-N″-methylureido)-4-piperidinyl]-1,3-benzenedimethanamineExample 97 AMD7131:N,N′-bis(2-pyridinylmethyl)-N-[N″-p-toluenesulfonylphenylalanyl)-4-piperidinyl]-1,3-benzenedimethanamineExample 98 AMD7136:N,N′-bis(2-pyridinylmethyl)-N-[1-[3-(2-chlorophenyl)-5-methylisoxazol-4-oyl]-4-piperidinyl]-1,3-benzenedimethanamineExample 99 AMD7138:N-[(2-hydroxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 100 AMD7140:N-[(4-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 101 AMD7141:N-[(4-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 102 AMD7142:N-[(4-acetamidophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 103 AMD7145:N-[(4-phenoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 104 AMD7147:N-[(1-methyl-2-carboxamido)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 105 AMD7151:N-[(4-benzyloxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 106 AMD7155:N-[(thiophene-2-yl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 107 AMD7156:N-[]-(benzyl)-3-pyrrolidinyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 108 AMD7159:N-[[1-methyl-3-(pyrazol-3-yl)]propyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 109 AMD7160:N-[1-(phenyl)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 110 AMD7164:N-[(3,4-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 111 AMD7166:N-[1-benzyl-3-carboxymethyl-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 112 AMD7167:N-[(3,4-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 113 AMD7168:N-(3-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 114 AMD7169:N-[[1-methyl-2-(2-tolyl)carboxamido]ethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 115 AMD7171:N-[(1,5-dimethyl-2-phenyl-3-pyrazolinone-4-yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 116 AMD7172:N-[(4-propoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 117 AMD7175:N-(1-phenyl-3,5-dimethylpyrazolin-4-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 118 AMD7177:N-[1H-imidazol-4-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 119 AMD7180:N-[(3-methoxy-4,5-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 120 AMD7182:N-[(3-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 121 AMD7184:N-[(3-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 122 AMD7185:N-(5-ethylthiophene-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 123 AMD7186:N-(5-ethylthiophene-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 124 AMD7187:N-[(2,6-difluorophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 125 AMD7188:N-[(2,6-difluorophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 126 AMD7189:N-[(2-difluoromethoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 127 AMD7195:N-(2-difluoromethoxyphenylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 128 AMD7196:N-(1,4-benzodioxan-6-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 129 AMD7197:N,N′-bis(2-pyridinylmethyl)-N-[1-(N″-phenyl-N″-methylureido)-4-piperidinyl]-1,4-benzenedimethanamineExample 130 AMD7198:N,N′-bis(2-pyridinylmethyl)-N-[N″-p-toluenesulfonylphenylalanyl)-4-piperidinyl]-1,4-benzenedimethanamineExample 131 AMD7199:N-[1-(3-pyridinecarboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 132 AMD7200:N-[1-(cyclopropylcarboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 133 AMD7201:N-[1-(1-phenylcyclopropylcarboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 134 AMD7202:N-(1,4-benzodioxan-6-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 135 AMD7203:N-[1-[3-(2-chlorophenyl)-5-methyl-isoxazol-4-carboxamido]-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 136 AMD7204:N-[1-(2-thiomethylpyridine-3-carboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 137 AMD7207:N-[(2,4-difluorophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 138 AMD7208:N-(1-methylpyrrol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 139 AMD7209:N-[(2-hydroxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 140 AMD7212:N-[(3-methoxy-4,5-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 141 AMD7216:N-(3-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 142 AMD7217:N-[2-(N″-morpholinomethyl)-1-cyclopentyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 143 AMD7220:N-[(1-methyl-3-piperidinyl)propyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 144 AMD7222:N-(1-methylbenzimidazol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 145 AMD7223:N-[1-(benzyl)-3-pyrrolidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 146 AMD7228:N-[[(1-phenyl-3-(N″-morpholino)]propyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 147 AMD7229:N-[1-(iso-propyl)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 148 AMD7230:N-[1-(ethoxycarbonyl)-4-piperidinyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 149 AMD7231:N-[(1-methyl-3-pyrazolyl)propyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 150 AMD7235:N-[1-methyl-2-(N″,N″-diethylcarboxamido)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 151 AMD7236:N-[(1-methyl-2-phenylsulfonyl)ethyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 152 AMD7238:N-[(2-chloro-4,5-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 153 AMD7239:N-[1-methyl-2-[N″-(4-chlorophenyl)carboxamido]ethyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 154 AMD7241:N-(1-acetoxyindol-3-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 155 AMD7242:N-[(3-benzyloxy-4-methoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 156 AMD7244:N-(3-quinolylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 157 AMD7245:N-[(8-hydroxy)-2-quinolylmethyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 158 AMD7247:N-(2-quinolylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 159 AMD7249:N-[(4-acetamidophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 160 AMD7250:N-[1H-imidazol-2-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 161 AMD7251:N-(3-quinolylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 162 AMD7252:N-(2-thiazolylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 163 AMD7253:N-(4-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 164 AMD7254:N-[(5-benzyloxy)benzo[b]pyrrol-3-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 165 AMD7256:N-(1-methylpyrazol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 166 AMD7257:N-[(4-methyl)-1H-imidazol-5-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 167 AMD7259:N-[[(4-dimethylamino)-1-napthalenyl]methyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 168 AMD7260:N-[1,5-dimethyl-2-phenyl-3-pyrazolinone-4-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 169 AMD7261:N-[1-[(1-acetyl-2-(R)-prolinyl]-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 170 AMD7262:N-[1-[2-acetamidobenzoyl-4-piperidinyl]-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 171 AMD7270:N-[(2-cyano-2-phenyl)ethyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 172 AMD7272:N-[(N″-acetyltryptophanyl)-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 173 AMD7273:N-[(N″-benzoylvalinyl)-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 174 AMD7274:N-[(4-dimethylaminophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 175 AMD7275:N-(4-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 176 AMD7276:N-(1-methylbenzimadazol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamineExample 177 AMD7277:N-[1-butyl-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 178 AMD7278:N-[1-benzoyl-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 179 AMD7290:N-[1-(benzyl)-3-pyrrolidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 180 AMD7309:N-[(1-methyl)benzo[b]pyrrol-3-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 181 AMD73 11:N-[1H-imidazol-4-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamineExample 182 AMD7359:N-[1-(benzyl)-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2 AMD7359:N-[1-(benzyl)-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2 Example 183AMD7374:N-[1-methylbenzimidazol-2-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 184 AMD7379:N-[(2-phenyl)benzo[b]pyrrol-3-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4-benzenedimethanamineExample 185 AMD9025:N-[(6-methylpyridin-2-yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineExample 186 AMD9031:N-(3-methyl-1H-pyrazol-5-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamineExample 187 AMD9032:N-[(2-methoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamineExample 188 AMD9039:N-[(2-ethoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,3-benzenedimethanamineExample 189 AMD9045:N-(benzyloxyethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamineExample 190 AMD9052:N-[(2-ethoxy-1-naphthalenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamineExample 191 AMD9053:N-[(6-methylpyridin-2-yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamineExample 192 96-well plating procedure

[0483] Solutions of test compounds (20 μM) were prepared inacetonitrile/methanol (1:1) using a pump dispenser. 5 μmoles of eachcompound were then dispensed into a single well of a Costar 96-wellplate by a Packard Multiprobe II-Ex Robotoc liquid handling system. Thesolvent was then removed under reduced pressure on a Savant Speed Vacfor 12 hours at room temperature.

Example 193 Inhibition of Chemokine Induced Ca Flux Measured on a FLIPR(Molecular Devices)

[0484] Reagents:

[0485] Loading dye: Fluo-3, AM (Molecular Probes F-1241) is dissolved inanhydrous DMSO and stored frozen in aliquots. To increase the solubilityof the dye in the loading medium, 10% (w/v) pluronic acid (MolecularProbes F-127) is added to the Fluo-3 stock solution immediately beforeuse.

[0486] Flux Buffer:

[0487] HBSS +20 mM Hepes buffer +0.2% BSA, pH 7.4. HBSS 10× [(w/o phenolred and sodium bicarbonate (Gibco 14 065-049)]; Hepes buffer 1M (Gibco15 630-056), BSA (Sigma A3675). The flux buffer is vacuum-filtered andstored refrigerated for a maximum of 5 days. Before use in theexperiment, the buffer is warmed at 37° C. in a waterbath.

[0488] Antagonists:

[0489] The test compounds were diluted in flux buffer and added to 4wells of a black microplate (4 parallel measurements per compound). Thefollowing control wells were used: 100% response control (noinhibition), flux buffer was added; 100% inhibition control: chemokinewas added at 5-times the concentration required to induce a Ca flux.

[0490] Preparation of the Agonist (Chemokine) Plate

[0491] The chemokines are diluted in flux buffer to concentrations thatare 4-fold higher than the desired concentrations required forstimulation of the cells (i.e. 2.5 nM for SDF-1α and 0.6 nM for RANTES).The chemokines were added to untreated 96-well Sero well compound plates(International Medical, Sterilin code 611F96). In the negative controlwell's (baseline monitoring), flux buffer is added instead of chemokine.As a positive control to check for dye loading efficiency, 20 μMdigitonin (final concentration) was also included. The agonist plate wasincubated in the FLIPR (37° C.) for 15-30 min.

[0492] Cell Loading Protocol for Measuring Inhibition of SDF-1α InducedCa flux in SUP-T1 Cells.

[0493] SUP-T1 cells were centrifuged at room temperature (RT) andre-suspended in loading medium (RPMI-1640 containing 2% FBS and 4 μMFluo-3, AM). The cells were incubate at room temperature for 45 min.then washed twice in flux buffer then incubated in flux buffer at roomteperature for 10 min. The cells were centrifuged and re-suspended influx buffer at a density of 3×10⁶ cells per mL. A 100 μL aliquot of thecell suspension (3×10⁵ cells) was added to each well of a blackmicroplate (Costar 3603), which already contains 50 μL of a solution ofthe test compound (at concentrations that are 3-fold higher than thedesired final compound concentrations). The microplate is then gentlycentrifuged at room temperature. Homogeneous spreading of the cells onthe bottom of the microplate wells was then confirmed with a microscopeand the microplate was incubated in the FLIPR (37° C.) for 10 min. priorto testing.

[0494] Fluorescence Measurements as a Function of Time on the FLIPR

[0495] The FLIPR settings (camera exposure time and laser power) areadjusted to obtain initial fluorescence values between 8,000 and 10,000units. After monitoring a 20 second-baseline, the agonist (chemokine)(50 μL) is added by automatic pipettor with black pipette tips.Fluorescence is measured simultaneously in all wells of the microplateevery 2 seconds (first 2 min) and thereafter every 6 seconds (additional2 min). The average ca-flux measured in each set of 4 identical wells(one test compound) was calculated by the FLIPR software.

[0496] The compounds of the current invention were tested for inhibitionof SDF-1α induced Ca flux in SUP-T1 cells using the method describedabove. The following compounds inhibited SDF-1α induced Ca flux greaterthan 20% at 20 μg/mL:

[0497] Example numbers: 7, 8, 9, 10, 12, 15, 16, 17, 18, 20, 22, 23(both isomers), 24, 26, 28, 29, 30, 31, 35, 37, 41, 43, 45, 47,48, 49,50, 51, 52, 53, 55, 60, 66, 72, 73, 75, 76, 77, 79, 82, 84, 85, 86, 88,89, 92,

[0498] The following compounds inhibited SDF-1α induced Ca flux greaterthan 20% at 20 μM:

[0499] Example numbers: 97, 98, 129, 130, 131, 133, 135, 136, 142, 145,146, 147, 150, 160, 164, 166, 167, 168, 169, 170, 172, 177, 178, 180,182, 183, 184.

Example 194 Cell Loading Protocol for Measuring Inhibition of RANTESInduced Ca Flux in U87.CCR5 Cells

[0500] U87.CCR5 cells were seeded into the black microplates (Costar3603) on the day before the experiment. The culture medium was removedfrom the cells and 100 μL of loading medium (DMEM+10% FBS+4 μM Fluo-3,AM) was added to each well and the plate was incubate at 37° C. for 45min. The loading medium was then removed an the cells were washed twicewith flux buffer using the CELLWASH microplate washer (Labsystems)followed by incubation in flux buffer for 10 min. at room temperature(the washing procedure was repeated twice). Finally, the wash buffer wasremoved from the microplate wells and 150 μL of the test compound,diluted in flux buffer to the desired concentration. The microplate wasthen incubated in the FLIPR drawer for 10 min. prior to testing.Measurements were performed as described above.

[0501] The compounds of the current invention were tested for inhibitionof RANTES induced Ca flux in U87.CCR5 cells. The following compoundsinhibited RANTES induced Ca flux greater than 20% at 20 μg/mL:

[0502] Example numbers: 5, 6, 7, 8, 11, 16, 22, 24, 25, 30, 38, 44, 47,49, 50, 52, 67, 68, 71, 73, 76, 77.

[0503] The following compounds inhibited RANTES induced Ca flux greaterthan 20% at 20 μM.

[0504] Example numbers: 108, 109, 114, 118, 168, 170, 179.

Example 195 Assay for Inhibition of HIV-1 (NL4.3) Replication in MT-4Cells

[0505] Inhibition of HIV-1 NL4.3 (or III_(B)) replication assays wereperformed as previously described (Bridger et al. J. Med. Chem. 1999,42, 3971-3981; De Clercq et al. Proc. Natl. Acad. Sci, 1992, 89,5286-5290; De Clercq et al. Antimicrob. Agents Chemother. 1994, 38,668-674; Bridger et al. J. Med. Chem. 1995, 38, 366-378). Anti-HIVactivity and cytotoxicity measurements were carried out in parallel.They were based on the viability of MT-4 cells that had been infectedwith HIV in the presence of various concentrations of the testcompounds. After the MT-4 cells were allowed to proliferate for 5 days,the number of viable cells was quantified by a tetrazolium-basedcolorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) procedure in 96-well microtrays. In all of these assays,viral input (viral multiplicity of infection, MOI) was 0.01, or 100times the 50% cell culture infective dose (CCID₅₀). The EC₅₀ was definedas the concentration required to protect 50% of the virus-infected cellsagainst viral cytopathicity.

[0506] When compounds of the current invention were tested forinhibition of HIV-1 NL4.3 or III_(B) replication in MT-4 cells, thefollowing compounds exhibited EC₅₀'s of less than 20 μg/mL:

[0507] Examples numbers: 1, 2, 3, 4, 6, 7, 8, 11, 12, 13, 14, 15, 16,17, 18, 19,20, 21, 23 (both isomers), 24, 28, 29, 30, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 47, 48, 49, 50, 51, 52, 53, 55,58, 61, 66, 67, 68, 69, 70, 71, 84, 85, 86, 88, 89, 91, 92.

[0508] When compounds of the current invention were tested forinhibition of HIV-1 NL4.3 or III_(B) replication in MT-4 cells, thefollowing compounds exhibited EC₅₀'s of less than 20 μM:

[0509] Example numbers: 95,96, 101, 102, 103, 105, 112, 113, 115, 116,119, 121, 123, 124, 125, 126, 137, 138, 139, 140, 141, 144, 151, 153,157, 158, 166, 170, 171, 176.

Example 196 Assay for Inhibition of HIV-1 (BaL) Replication in PBMC's

[0510] When compounds of the current invention were tested forinhibition of HIV-1 BaL (CCR5 using) replication in PHA-stimulatedPBMC's (peripheral blood mononuclear cells) using the MTT assay, thefollowing compounds exhibited EC₅₀'s of less than 20 μg/mL:

[0511] Example numbers: 5, 8, 11, 12, 13, 14, 17, 29, 30, 32, 33, 34,36, 37, 42, 43, 58, 66, 71, 88, 91. TABLE 3 EXAMPLE 197 1-[[4-[[(2-AMD7074: pyridinylmethyl)amino]methyl] phenyl]methyl]guanidine EXAMPLE198 N-(2-pyridinylmethyl)-N-(8-methyl-8- AMD7076:azabicyclo[3.2.1]octan-3-yl)-1,4- benzenedimethanamine EXAMPLE 1991-[[4-[[(2- AMD7078: pyridinylmethyl)amino]methyl]phenyl]methyl]homopiperazine EXAMPLE 200 1-[[3-[[(2- AMD7079:pyridinylmethyl)amino]methyl] phenyl]methyljhomopiperazine EXAMPLE 201trans and cis-1-[[4-[[(2- AMD7103 andpyridinylmethyl)amino]methyl]phenyl]methyl]- 7104: 3,5-piperidinediamineEXAMPLE 202 N,N′-[1,4-Phenylenebis(methylene)]bis-4-(2- AMD3597:pyrimidyl) piperazine EXAMPLE 203 1-[[4-[[(2- AMD3602:pyridinylmethyl)amino]methyl]phenyl]methyl]- 1-(2-pyridinyl)methylamineEXAMPLE 204 2-(2-pyridinyl)-5-[[(2- AMD3667:pyridinylmethyl)amino]methyl]-1,2,3,4- tetrahydroisoquinoline. EXAMPLE205 1-[[4-[[(2- AMD7428: pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diaminopyrrolidine EXAMPLE 206 1-[[4-[[(2- AMD7485:pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diacetylaminopyrrolidine EXAMPLE 207 8-[[4-[[(2- AMD8665:pyridinylmethyl)amino]methyl]phenyl]methyl]-2,5,8-triaza-3-oxabicyclo[4.3.0]nonane EXAMPLE 208 8-[[4-[[(2- AMD8773:pyridinylmethyl)amino]methyl]phenyl]methyl]-2,5,8-triazabicyclo[4.3.0]nonane

Example 197 AMD7074: Preparation of1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]guanidine(hydrobromide salt)

[0512] α-Bromo-p-toluamide

[0513] α-Bromo-p-toluic acid (8.00 g, 37.2 mmol) was stirred as asuspension in CCl₄ (80 mL) while thionyl chloride (6.8 mL, 93 mmol) wasadded. The mixture was heated at reflux under nitrogen atmosphere for 95h., then concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (150mL), and NH₃(g) was passed through the solution for 10 min, giving alight yellow precipitate. 5% NaHCO₃(aq) (70 mL) was added, the mixturewas stirred vigorously, and the precipitate was collected by filtration.The precipitate was washed with H₂O and dried at 60° C. under reducedpressure to give a colourless solid (7.35 g, 92%).

[0514] N-(Diethoxyphosphoryl)-2-(aminomethyl)pyridine.

[0515] A solution of 2-(aminomethyl)pyridine (8.03 g, 74.3 mmol) andEt₃N (13.50 mL, 96.86 mmol) in CH₂Cl₂ (60 mL) was stirred at roomtemperature while a solution of diethyl chlorophosphate (Dep-Cl) (14.09g, 81.66 mmol) in CH₂Cl₂ (30 mL) was added dropwise. The mixture washeated to reflux for 21 h, allowed to cool, then washed with H₂O (50mL). The aqueous phase was extracted with CH₂Cl₂ (20 mL), and thecombined organic phases were dried (MgSO₄) and concentrated in vacuo.Diethyl ether (100 mL) was added to the residue giving a whiteprecipitate, which was removed by filtration, and the filtrate was thenconcentrated in vacuo to give the product as an orange oil (18.04 g,100%).

[0516] A solution of N-(diethoxyphosphoryl)-2-(aminomethyl)pyridine(7.45 g, 30.5 mmol) in DMF (70 mL) was treated with 95% NaH (0.96 g, 38mmol) and stirred under nitrogen atmosphere at room temperature for 10min. A solution of α-bromo-p-toluamide (6.40 g, 29.9 mmol) in DMF (30mL) was added in one portion, and the solution was stirred for 1 h. Thesolution was concentrated in vacuo and the residue was partitionedbetween 5% aqueous NaHCO₃ (25 mL) and EtOAc (100 mL). The organic phasewas washed with 5% NaHCO₃ (25 mL). The combined aqueous phases wereextracted with EtOAc (25 mL). The combined organic phases were washedwith brine (5×25 mL), then dried (MgSO₄) and concentrated in vacuo togive the amide as a yellow oil (9.71 g, 86%).

[0517] 1-[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methylamine

[0518] A 1.0 M BH₃.THF solution (150 mL, 150 mmol) was added to theamide (8.85 g, 23.5 mmol), and the solution was heated at reflux undernitrogen atmosphere for 3.5 h, then concentrated in vacuo. MeOH (50 mL)was added to the residue, then removed in vacuo (3×). Ethylene diamine(20 mL) was added to the residue, and the solution was stirred at 60° C.for 1 h. The solution was diluted with CHCl₃ (150 mL) and washed withH₂O (4×200 mL), then dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by column chromatography on basic alumina (2%MeOH/CH₂Cl₂) to give the title amine as a light yellow oil (3.03 g,36%).

[0519] A heterogeneous mixture of the amine (140 mg, 0.385 mmol),1H-pyrazole-1-carboxanidine hydrochloride (55 mg, 0.38 mmol), and DIEA(0.067 mL, 0.38 mmol) in THF (0.19 mL) was stirred at room temperatureunder nitrogen atmosphere for 2 hours. Diethyl ether (5 mL) was added tothe mixture, then decanted (4×) to give a colourless oil that was driedin vacuo at room temperature to give the corresponding guanidinehydrochloride salt (170 mg, 100%).

[0520] Using general procedure D: A solution of the hydrochloride salt(170 mg, 0.38 mmol) was converted to the corresponding hydrobromide saltas a white solid (143 mg, 65% overall yield from the amine): ¹H NMR(D₂O) δ 4.44 (s, 2H), 4.47 (s, 2H), 4.63 (s, 2H), 7.43 (d, 2H, J=8.1),7.52 (d, 2H, J=8.3), 7.90 (m, 2H), 8.39 (m, 1H), 8.76 (m, 1H). FAB-MS270 (M+H). Anal. Calcd for C₁₅H₁₉N₅.3.0HBr.0.8AcOH.0.8H₂O (574.54): C,34.70; H, 4.70; N, 12.19; Br, 41.72. Found: C, 34.66; H, 4.73; N, 12.17;Br, 41.82.

Example 198 AMD7076: Preparation ofN-(2-pyridinylmethyl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1,4-benzenedimethanamine(hydrobromide salt)

[0521] Tropinone Oxime

[0522] A heterogeneous mixture of tropinone (7.07 g, 50.8 mmol),hydroxylamine hydrochloride (3.53 g, 50.8 mmol), and pyridine (8.20 mL,101 mmol) in EtOH (100 mL) were heated at reflux for 50 min. The mixturewas slightly cooled, treated with K₂CO₃ (21.24 g, 153.7 mmol) and H₂O(30 mL), then concentrated in vacuo. The residue was diluted with H₂O(30 mL), then extracted with CHCl₃ (3×50 mL). The combined organicextracts were dried (MgSO₄) and concentrated in vacuo. The residue wasrecrystallized from 4:6 EtOAc/petroleum ether to give colourlesscrystals (5.18 g, 66%).

[0523] exo-Tropylamine (beta-tropylamine)

[0524] A solution of tropinone oxime (5.17 g, 33.5 mmol) in 1-pentanol(170 mL) was heated at 130° C. under nitrogen atmosphere and a refluxcondenser while sodium (5.28 g, 230 mmol) was added portionwise over 1hours. The solution was allowed to cool to room temperature and stirringwas continued for a further 17 hours. The solution was acidified with 6M HCl (112 mL) and extracted with EtOAc (1×240 mL, 3×120 mL). Theaqueous solution was basified to pH 14 using NaOH, then extracted withEtOAc (6×120 mL). The combined organic extracts were dried (K₂CO₃) andconcentrated in vacuo to give the amine as a yellow oil (3.49 g, 74%).

[0525] A solution of exo-tropylamine (596 mg, 4.25 mmol) andN-[1-methylene-4-(carboxaldehyde)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(1.74 g, 4.23 mmol) in MeOH (20 mL) was heated at reflux under nitrogenatmosphere for 2.5 hours. The solution was allowed to cool to 60° C. andNaBH₃CN (1.37 g, 21.8 mmol) was added, and the solution was stirred at60° C. for 24 hours. The solution was concentrated in vacuo, and theresidue was partitioned between CH₂Cl₂ (25 mL) and brine (25 mL). Theaqueous phase was extracted with CH₂Cl₂ (2×25 mL), and the combinedorganic phases were dried (MgSO₄) and concentrated in vacuo to give ayellow solid (2.17 g, 96%).

[0526] The solid from above was dissolved in Et₃N (2.30 mL, 16.5 mmol)and CH₂Cl₂ (20 mL) and 2-nitrobenzenesulfonyl chloride (2.68 g, 12.1mmol) was added in one portion. The mixture was heated to reflux undernitrogen for 21 hours. Further portions of 2-nitrobenzenesulfonylchloride (2.68 g, 12.1 mmol) and Et₃N (2.30 mL, 16.5 mmol) were added tothe solution, and heating was continued for an additional 24 hours. Thesolution was diluted with CH₂Cl₂ (30 mL) and washed with H₂O (50 mL).The aqueous phase was extracted with CH₂Cl₂ (3×50 mL), and the combinedorganic phases were washed with brine (4×50 mL), then dried (MgSO₄) andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 10% MeOH/CH₂Cl₂ to give a yellow solid (513 mg, 18%).

[0527] Using general procedures C and D: the intermediate from above(252 mg, 0.350 mmol) was reacted with thiophenol (0.22 mL, 2.1 mmol) andK₂CO₃ (390 mg, 2.82 mmol) in CH₃CN (3.5 mL) and the mixture was heatedat 50° C. under nitrogen atmosphere for 22 hours. The insoluble materialwas removed by filtration and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuo, and the residue was purified by chromatography onbasic alumina using CH₂Cl₂ and 10% MeOH/CH₂Cl₂ to give a yellow oil (87mg, 71%). Conversion to the hydrobromide salt using a saturated solutionof HBr in methanol followed by drying of the solid at 60° C. underreduced pressure for 87 hours gave AMD7076 as beige solid (99 mg, 58%).¹H NMR (D₂O) δ 2.06-2.51 (m, 8H), 2.82 (s, 3H), 3.84 (m, 1H), 4.11 (brs, 2H), 4.34 (s, 2H), 4.46 (s, 2H), 4.60 (s, 2H), 7.59 (s, 4H), 7.82 (m,2H), 8.29 (m, 1H), 8.74 (m, 1H). FAB-MS m/z 351 (M+H). Anal. Calcd forC₂₂H₃₀N₄.4.0HBr.2.1H₂O (711.99): C, 37.11; H, 5.41; N, 7.87; Br, 44.89.Found: C, 37.19; H, 5.48; N, 7.79; Br, 44.90.

Example 199 AMD7078: Preparation of1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]homopiperazine(hydrobromide salt)

[0528] A mixture of K₂CO₃ (388.4 mg, 2.18 mmol),N-[1-methylene-4-(chloromethylene)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(Bridger et al. U.S. patent application Ser. No. 09/111/895) (404.6 mg,0.937 mmol) and homopiperazine (281.5 mg, 2.18 mmol) in CH₃CN (25 mL)was heated to reflux with stirring overnight. The solvent was evaporatedand the residue was partitioned between saturated aqueous NaHCO₃ andCH₂Cl₂. The aqueous phase was separated and extracted with CH₂Cl₂ andthe combined organic extracts were dried (MgSO₄) and evaporated. Theresidue was purified by column chromatography on silica gel (40:2:1 or20:2:1 CHCl₃/MeOH/NH₄OH) to give the title compound (352.3 mg, 76%). ¹H(CDCl₃) δ 8.40 (d, 1H, J=6 Hz), 7.98 (d, 1H, J=9 Hz), 7.66 (m, 2H), 7.54(m, 2H), 7.20 (m, 3H), 7.09 (m, 3H), 4.61 (s, 2H), 4.59 (s, 2H), 3.58(s, 2H), 2.72-2.68 (m, 2H), 2.51 (s, 2H), 1.70-1.56 (m, 6H).

[0529] Using general procedures C and D: the intermediate from abovegave AMD7078. ¹H NMR (D₂O) δ 8.75 (d, 1H, J=5 Hz), 8.33 (t, 1H, J=8 Hz),7.90-7.81 (m, 2H), 7.64-7.61 (m, 4H), 4.63 (s, 2H), 4.54 (s, 2H), 4.49(s, 2H), 3.79-3.72 (m, 4H), 3.56-3.49 (m, 4H), 2.33-2.29 (m, 2H). ¹³CNMR (D₂O): δ 147.6, 146.7, 143.9, 132.9, 132.6, 131.5, 130.5, 126.9,126.8, 61.0, 54.3, 51.3, 50.3, 49.1, 45.1, 41.0, 21.0. ES-MS m/z 311(M+H). Anal. calcd. for C₁₉H₂₆N₄.4HBr.1.2HOAc.0.7 H₂O: C 35.76, H 5.08,N 7.79, Br 44.47; found C 35.71, H 5.40, N 7.74, Br 44.56.

Example 200 AMD7079: Preparation of1-[[3-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]homopiperazine(hydrobromide salt)

[0530] Using identical procedures to those described in Example 199,N-[1-methylene-3-(chloromethylene)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridinegave AMD7079. ¹H NMR (D₂O) δ 8.72 (d, 1H, J=5 Hz), 8.24 (t, 1H, J=8 Hz),7.83-7.74 (m, 2H), 7.66-7.60 (m, 4H), 4.59 (s, 2H), 4.54 (s, 2H), 4.48(s, 2H), 3.76-3.69 (m, 4H), 3.61-3.48 (m, 4H), 2.30-2.28 (m, 2H). ¹³CNMR (D₂O): δ 147.9, 147.0, 142.5, 132.8, 132.7, 132.1, 131.6, 130.6,126.5, 126.1, 126.0, 60.7, 53.8, 50.9, 49.9, 49.2, 44.7, 40.6, 20.7.ESMS: 311 (M+H). Anal calcd for C₁₉H₂₆N₄.4HBr.1.0C₄H₈O₂.2.3H₂O: C 36.18,H 5.62, N 7.34, Br 41.85. Found: C 36.25, H 5.63, N 7.34, Br 41.85.

Example 201 AMD7103 and 7104: Preparation of trans andcis-1-[[4-[[(2-pyridinylmethy)amino]methyl]phenyl]methyl]-3,5-piperidinediamine(hydrobromide salts)

[0531] 3,5-Diaminopyridine

[0532] 2-Chloro-3,5-dinitropyridine (4.98 g, 24.46 mmol) was dissolvedin ethanol (500 mL) and 5% palladium on carbon (3.74 g, 0.75 g/gsubstrate) was added. The mixture was hydrogenated at 25° C. under 50psi of hydrogen for 18 hrs. The mixture was filtered through celite toremove the catalyst and concentrated under reduced pressure.Purification (silica gel, 20:2:1 CHCl₃/MeOH/NH₄OH, followed by 12:2:1CHCl₃/MeOH/NH₄OH) gave 3,5-diaminopyridine (2.27 g, 85%) as a brownsolid. ¹H (CD₃OD) δ 7.32 (d, 2H, J=2 Hz), 6.45-6.43 (m, 1H).

[0533] 3,5-bis(ethoxycarbonylamino)pyridine

[0534] 3,5-diaminopyridine (381.4 mg, 3.49 mmol) was dissolved inanhydrous 1,4-dioxane (6 mL) and K₂CO₃ (1.45 g, 10.5 mmol) was added,followed by ethyl chloroformate (1.0 mL, 10.5 mmol). The thick slurrywas heated at reflux for 22 hrs. The solvent was removed under reducedpressure, the residue was taken up in methanol and filtered throughcelite. Purification (silica gel, 9:1 CH₂Cl₂/MeOH) gave thebis-carbamate (608 mg, 69%) as a light brown solid. ¹H (CD₃OD) δ 8.37(s, 2H), 8.28-8.27 (m, 1H), 4.22 (q, 4H, J=7 Hz), 1.31 (t, 6H, J=7 Hz).

[0535] Cis and trans-3,5-bis(ethoxycarbonylamino)piperidine.

[0536] The compound from above (5.09 g, 20.1 mmol) was dissolved inglacial acetic acid (200 mL) and concentrated HCl (1.65 mL, 20.1 mmol)was added. After agitation of the solution, Platinum(IV) Oxide (1.60 g,7.04 mmol) was added and the mixture was hydrogenated at 25° C. under 50psi of hydrogen for 41 hrs. The solution was then heated to 50° C. andhydrogenated under 50 psi for an additional 20 hrs. An additional batchof the above intermediate (1.10 g, 4.34 mmol) was reduced byhydrogenating at 50° C. under 50 psi of hydrogen pressure for 22 hrs.The two batches were combined, filtered through celite and concentrated.The HCl salt was converted to the free base by stirring with K₂CO₃ (500mg) in MeOH (50 mL). ¹H NMR analysis of the crude product indicated a˜80:20 trans to cis mixture of piperidines. The two isomers wereseparated by column chromatography (silica gel, 20:2:1 CHCl₃/MeOH/NH₄OH)to give the trans product (1.67 g, 26%) and cis product (205.5 mg, 3%).

[0537] trans-3,5-bis(ethoxycarbonylamino)piperidine: ¹H (CD₃OD) δ 4.09(q, 4H, J=7 Hz), 3.58-3.48 (m, 2H), 3.05 (dd, 2H, J=12 Hz, 3 Hz), 2.18(t, 3H, J=12 Hz), 1.22 (t, 5 H, J=7 Hz).

[0538] cis-3,5-bis(ethoxycarbonylamino)piperidine. ¹H (CD₃OD) δ 4.07 (q,4H, J=7 Hz), 3.73-3.3.66 (m, 2H), 2.87 (dd, 2H, J=13 Hz, 3 Hz),2.63-2.56 (m, 2H), 1.79 (t, 2H, J=6 Hz), 1.24 (t, 5 H, J=7 Hz).

[0539] The intermediates from above were reacted with the intermediateand conditions described in Example 199. Using general procedures C andD: the nosyl group was deprotected with thiophenol and the correspondingamine intermediate was converted to the hydrobromide salt (HBr/aceticacid, 50° C.) with simultaneous deprotection of the ethoxycarbonylgroups to give the following compounds:

[0540] AMD7 103:trans-1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,5-piperidinediamine(hydrobromide salt). ¹H NMR (D₂O) δ 8.78 (d, 1H, J=5 Hz), 8.38 (t, 1H,J=7 Hz), 7.96-7.86 (m, 2H), 7.65 (s, 4H), 4.65 (s, 2H), 4.56 (s, 2H),4.50 (s, 2H), 3.85-3.75 (m, 4H), 3.20 (t, 2H, J=10 Hz), 2.69 (d, 1H,J=12 Hz), 1.95 (q, 1H, 12 Hz). ¹³C NMR (D₂O) δ 147.3, 146.4, 144.5,132.9, 132.7, 131.5, 130.4, 127.2, 127.2, 61.5, 51.8, 51.4, 49.0, 44.0,30.9. ES-MS m/z 326 (M+H).

[0541] AMD7 104:cis-1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,5-piperidinediamine(hydrobromide salt). ¹H NMR (D₂O): δ 8.73 (d, 1H, J=5 Hz), 8.27 (t, 1H,J=7 Hz), 7.85-7.63 (m, 2H), 7.52 (s, 4H), 4.79 (s, 2H), 4.56 (s, 2H),4.43 (s, 2H), 3.83-3.78 (m, 2H), 3.03 (d, 2H, J=11 Hz), 2.81-2.75 (m,2H), 2.17 (t, 1H, J=6 Hz). ¹³C NMR (D₂O) δ 150.5, 149.5, 145.8, 140.1,133.4, 133.3, 133.0, 129.2, 129.1, 63.6, 56.3, 53.9, 51.6, 47.4, 32.6.ES-MS m/z 326 (M+H). Anal. calcd. for C₁₉H₂₇N₅.5.6HBr.0.2H₂O: C 29.18, H4.25, N 8.95, Br 57.21; found C 29.36, H 4.61, N 8.76, Br 57.04.

Example 202 AMD3597: Preparation ofN,N′-[1,4-Phenylenebis(methylene)]bis-4-(2-pyrimidyl)piperazine(hydrobromide salt)

[0542] Reaction of α,α′-dibromo-p-xylene with 1-(2-pyrimidyl)piperazinedihydrochloride and potassium carbonate in acetonitrile in a similarmanner to example 199, followed by conversion to the correspondinghydrobromide salt using general procedure D gave AMD3597. ¹H NMR (D₂O) δ2.80-3.70 (m, 16H), 4.32 (s, 4H), 6.79 (m, 2H), 7.50 (s, 4H), 8.38 (m,4H); ¹³C NMR (D₂O) δ 41.92, 50.57, 60.13, 111.46, 130.29, 132.51,153.94, 157.36. FAB-MS m/z 431 (M+H). Anal. Calcd forC₂₄H₃₀N₈.4HBr.2.5H₂O: C, 36.07; H, 4.92; N, 14.02; Br, 39.99. Found C,36.04; H, 4.80; N, 13.91; Br, 39.94.

Example 203 AMD3602: Preparation of1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-1-(2-pyridinyl)methylamine(hydrochloride salt)

[0543] To a stirred solution of p-tolylmagnesium bromide (1.0 M solutionin ether, 98 mL, 0.098 mol) cooled to 0° C. was added 2-cyanopyridine(5.1 g, 0.04 mol) in ether (90 mL) and the mixture was heated to refluxfor 40 hours. The reaction was allowed to cool to room temperature thenquenched with a mixture of concentrated sulfuric acid/water (1:1, 30mL). The mixture was stirred for twenty minutes and the ether layer wasseparated. The aqueous phase was made basic with aqueous 10 N NaOH (topH 8) then extracted with CH₂Cl₂. The combined organic extracts weredried (MgSO₄) and evaporated to give the crude product as a yellow oil(6.69 g, 69%). This was used without further purification in the nextstep.

[0544] To the ketone from above (2.02 g, 0.01 mol) in a mixture oft-butanol (60 mL) and water (20 mL) was added KMnO4 (16.2 g, 0.1 mol)and the mixture was heated to reflux for 48 hours. The reaction mixturewas filtered (hot) through celite, and the celite was washed with hotwater and t-butanol. The combined filtrates were concentrated to smallvolume and extracted with dichloromethane. The aqueous phase was thenacidified to pH4 during which time a white solid precipitated. The solidwas collected by filtration, washed with water then dried in vacuo togive the corresponding acid (1.69 g, 73%) as a white powder.

[0545] To a stirred solution of the acid from above (7.07 g, 0.03 mol)in DMF (80 mL), cooled to 0° C. was added hydroxybenzotriazole (4.21 g,0.03 mol) and 2-(aminoethyl)pyridine (3.72 mL, 0.03 mol) followed bydiisopropylcarbodiimide (4.88 mL, 0.03 mol) and the mixture was stirredat 4° C. for 48 hours. The reaction mixture was evaporated and theresidue was suspended in water and acidified to pH1 with aqueous HCl.The aqueous layer was extracted with CH₂Cl₂ (6×100 mL) then made basicwith 1N NaOH to pH 8. The basic phase was extracted with CH₂Cl₂ (6×100mL) and the combined organic phases were dried (MgSO₄) and evaporated togive the crude product as a white solid (5.12 g).

[0546] To a solution of the ketone from above (2.55 g, 7.7 mmol) inethanol (60 mL), water (17 mL) and pyridine (0.03 mol, 2.5 mL) was addedhydroxylamine hydrochloride (2.14 g, 0.03 mol) and the mixture washeated to reflux for 2 hours. The reaction mixture was allowed to coolto room temperature during which time a white solid precipitated. Thesolid was collected by filtration, re-crystallized from ethanol/waterand dried in vacuo to give the corresponding oxime (2.12 g).

[0547] The oxime (2.0 g, 5.8 mmol) was dissolved in ethanol (140 mL) andmethanol (120 mL) containing Pd/C (Aldrich, 10%; 1.0 g) and the mixturewas hydrogenated at 50 psi overnight. The mixture was filtered throughcelite and concentrated to give the amine as a white solid (1.88 g).

[0548] The amine (0.5 g, 1.51 mmol) was dissolved in anhydrous THF (15mL) and a solution of BH₃.THF was added (Aldrich, 1.0 M solution in THF,10 equivalents, 15.05 mL) and the mixture was heated to reflux withstirring overnight. The mixture was allowed to cool to room temperatureand evaporated. Anhydrous methanol was added (10 mL) and the mixture wasevaporated (repeated 4 times). The residue was dissolved inethylenediamine (10 mL) and the mixture was heated to 100° C. overnight.Upon cooling, water (10 mL) was added and the solution was extractedwith CH₂Cl₂ (3×). The combined organic extracts were dried (MgSO₄) andevaporated to give an oil (0.205 g).

[0549] A portion of the crude product (140 mg) was purified by columnchromatography on silica gel (93:7:1, CH₂Cl₂MeOH/NH₄OH) to give a lightyellow oil (100 mg). The oil was dissolved in ethanol and HCl(g) waspassed through to give a precipitate which was collected by filtration.Trituration of the filtrate with ether gave a second crop of product (30mg). The solids were combined and dried in vacuo to give AMD3602 as apink solid (115 mg). ¹H NMR (D₂O) δ 3.20-3.50 (m, 4H), 4.18 (s, 2H),5.66 (s, 1H), 7.25-7.38 (m, 6H), 7.60-7.80 (m, 3H), 8.35 (m, 1H), 8.44(m, 1H), 8.53 (m, 1H). FAB-MS m/z 319 (M+H, 100). Anal. Calcd forC₂₀H₂₂N₄.4HCl.0.6EtOH: C, 51.76; H, 6.06; N, 11.39. Found C, 52.16; H,6.23; N, 11.73.

Example 204 AMD3667: Preparation of2-(2-pyridinyl)-5-[[(2-pyridinylmethyl)amino]methyl]-1,2,3,4-tetrahydroisoquinoline(hydrobromide salt)

[0550] 2-(3-hydroxyphenyl)ethylamine hydrochloride

[0551] To a stirred solution of 2-(3-methoxyphenyl)ethylamine (10.0 g,66.2 mmol) in dry CH₂Cl₂ (100 mL) at −78° C. was added a 1M solution ofBBr₃ in CH₂Cl₂ (200 mL, 3 eq.) and the solution was allowed to slowlywarm to RT. After stirring for 3 h at RT the resulting precipitate wasfiltered off, washed with CH₂Cl₂ (200 mL) and dried. The off-white solidwas dissolved in cold H₂O (50 mL) and the insoluble material wasfiltered off. The acidic filtrate (pH 1.2) was made basic (pH 13.0) with10 N NaOH and the resulting yellow solution was extracted with ether(100 mL) and the organic layer was discarded. The aqueous layer wasre-acidified with conc. HCl to pH 1.5 and then made alkaline (pH 9-10)with conc. NH₄OH. The aqueous layer was then extracted with n-butanol(2×150 mL), dried (K₂CO₃) and concentrated to dryness to afford aviscous oil. The oily residue was then dissolved in MeOH (10 mL) and asolution of saturated HCl/MeOH was added. The solution was concentratedto small volume and ether was added to give a precipitate. The ether wasdecanted off to afford the desired compound as an off white solid (6.5g, 57%). ¹H NMR (D₂O) 2.79 (t, 2H, J=7.2 Hz), 3.08 (t, 2H, J=7.2 Hz),6.60-6.78 (m, 3H), 7.11 (t, 1H, J=7.7 Hz).

[0552] To a stirred solution of 2-(3-hydroxyphenyl)ethylaminehydrochloride (4.0 g, 23.1 mmol) in ethanol (50 mL) under argon at roomtemperature was added Et₃N (23.2 g, 231 mmol) followed bypyridine-2-carboxaldehyde (2.47 g, 23.1 mmol) and the solution wasstirred at 40° C. for 16 h. The mixture was concentrated to dryness andthe residue was purified by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH; 90:10:1) to afford the crude product. The crude wasre-purified by chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH;95:5:0.5) to afford the desired product (580 mg, 11%) as a pale yellowsolid. ¹H NMR (CDCl₃) 2.59 (dt, 1H, J=16.5, 4.2 Hz), 2.75-2.89 (m, 1H),2.94-3.06 (m, 1H), 3.20 (dt, 1H, J=12.4, 5.0 Hz), 5.16 (s, 1H), 6.11 (d,1H, J=1.9 Hz), 6.60-6.52 (m, 2H), 7.24-7.32 (m, 2H), 7.66-7.74 (m, 1H),8.06 (d, 1H, J=4.7 Hz).

[0553] To a stirred solution of the amine (550 mg, 2.43 mmol) inanhydrous CH₂Cl₂ (30 mL) was added di-t-butyl dicarbonate (531 mg, 2.43mmol) and the solution was stirred at room temperature for 16 hours. Thereaction mixture was washed with water, dried over MgSO₄, andconcentrated to afford the product (700 mg, 80%) as a pale yellow solid.¹H NMR (CD₃OD) 1.42 (br s, 9H), 2.70-2.93 (br m, 2H), 3.78 (br s, 2H),5.98 (br s, 1H), 6.55-6.61 (m, 2H), 6.99 (d, 1H, J=8.2 Hz), 7.22 (m,1H), 7.40 (d, 1H, J=7.8 Hz), 7.75 (t, 1H, J=7.4 Hz), 8.44 (d, 1H, J=4.2Hz).

[0554] To a stirred solution of the phenol from above (230 mg, 0.71mmol) in pyridine (10 mL) cooled to 0° C. was added triflic anhydride(259 mg, 0.92 mmol) and the mixture was stirred for 1 h at 0° C. andthen for 16 h at room temperature. The solvent was concentrated and theresidue was dissolved in CH₂Cl₂ (50 mL) and washed with H₂O (2×25 mL).The organic layer was dried (MgSO₄) and evaporated to give a dark oil(300 mg, 92%). ¹H NMR (CDCl₃) 1.42 (br s, 9H), 2.86-3.03 (m, 2H),3.62-3.78 (m, 1H), 4.08 (br s, 1H), 6.03-6.38 (m, 1H), 7.01-7.12 (m,2H), 7.14-7.18 (m, 1H), 7.21-7.30 (m, 1H), 7.38 (br s, 1H), 7.62-7.71(m, 1H), 8.50 (d, 1H, J=4.5 Hz). This was used without furtherpurification in the next step.

[0555] To a stirred solution of the triflate from above (300 mg, 0.66mmol) in dry THF (5 mL) was added excess 2-aminomethylpyridine (1.0 g,9.2 mmol), PdCl₂ (4.6 mg, 4 mol %) and PPh₃ (13.7 mg, 8 mol %). Thereaction mixture was the pressurized to 60 psi with CO (g) and stirredfor 16 h at 100° C. The reaction mixture was then concentrated and theresidue was dissolved in CH₂Cl₂ (50 mL) and washed with H₂O (2×25 mL),brine (25 mL), dried (MgSO₄) and concentrated to afford the crudeproduct. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH; 95:5) afforded the desired compound (190 mg, 66%) as aviscous oil. ¹H NMR (CDCl₃) 1.41 (br s, 9H), 2.97 (br s, 2H), 3.75 (brs, 1H), 4.03 (br s, 1H), 4.72 (d, 2H, J=4.9 Hz), 6.13-6.34 (m, 1H),7.12-7.32 (m, 4H), 7.38 (s, 1H), 7.61-7.74 (m, 5H), 8.16-8.58 (m, 2H).

[0556] To a stirred solution of the amide from above (160 mg, 0.36 mmol)in anhydrous THF (3 mL) was added BH₃.THF (1M solution in THF, Aldrich,3.6 mL, 3.6 mmol) and the resulting mixture was heated to reflux for 18hours. The mixture was concentrated, MeOH was added to the residue andthe solution was evaporated once again. This procedure was repeated 5times. ¹H NMR of the crude residue indicated that the product wasobtained as a borane adduct. Thus, ethylene diamine (5 mL) was added tothe residue and the mixture was stirred at 100° C. for 18 h. Thereaction mixture was concentrated, water (5 mL) was added and the pH wasadjusted to pH 13 with 10 N NaOH. The aqueous phase was extracted withCH₂Cl₂ (2×100 mL), dried (MgSO₄) and concentrated to afford the crudeproduct. Purification by preparative TLC on a silica gel plate(CH₂Cl₂/MeOH, 95:5) afforded the desired compound (18.3 mg, 12%) as aviscous oil. ¹H NMR (CDCl₃) 1.37 (br s, 9H), 2.92 (br s, 2H), 3.75 (brs, 1H), 3.80 (s, 2H), 3.93 (s, 2H), 4.01 (br s, 1H), 5.92-6.21 (m, 1H),7.05-7.21 (m, 5H), 7.30 (d, 1H, J=7.8 Hz), 7.37 (br s, 1H), 7.57-7.68(m, 2H), 8.48-8.57 (m, 2H).

[0557] To a stirred solution of the Boc-amine from above (18.0 mg, 0.04mmol) in glacial acetic acid (1 mL) was added a solution of freshlyprepared HBr/glacial acetic acid (1 mL) and the solution was stirred atroom temperature for 18 hours. Ether was then added, resulting in theformation of a white precipitate. The solid was washed with ether bydecantation (3×) and dried in vacuo to afford AMD3667 as white solid (22mg, 80%). ¹H NMR (D₂O) δ 2.97-3.14 (m, 2H), 3.27-3.49 (m, 2H), 4.21 (s,2H), 4.35 (s, 2H), 5.78 (s, 1H), 6.82 (d, 1H, J=8.2 Hz), 7.14 (d, 1H,J=8.4 Hz), 7.27 (s, 1H), 7.35-7.48 (m, 2H), 7.50-7.58 (m, 2H), 7.85 (td,1H, J=7.7, 1.7 Hz), 8.01 (td, 1H, J=7.7, 1.7 Hz), 8.41 (dd, 1H, J=5.7,0.8 Hz), 8.50 (dd, 1H, J=5.7, 0.8 Hz). FAB-MS m/z 331 (M+H); Anal. Calcdfor C₂₁H₂₂N₄.4HBr.2H₂O: C, 36.55; H, 4.38; N, 8.12. Found C, 36.86; H,4.41; N, 8.33.

Example 205 AMD7428: Preparation of1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diaminopyrrolidine(hydrobromide salt)

[0558] To a solution of 3-pyrroline (1.0 g, 14.5 mmol) in 0° C. THF (50mL) and water (20 mL) mixture was added di-tert-butyldicarbonate (4.75g, 21.8 mmol) over a ten minute period. The resulting solution was thenstirred for 3 hours, gradually warming to room temperature. Ethylacetate (100 mL) was then added to the reaction, and the aqueous andorganic layers were separated. Following extraction of the aqueous layerwith a second portion of ethyl acetate, the combined organic fractionswere washed with 10% citric acid and then brine. The solution was thendried and concentrated to afford N-Boc-3-pyrroline in quantitativeyield.

[0559] The N-Boc-3-pyrroline (675 mg, 4.0 mmol) was then dissolved inanhydrous THF (8 ml). To this solution was added N-methylmorpholineoxide (468 mg, 4.0 mmol) and a solution of osmium tetroxide in t-butanol(1 mL of a 2.5% w/v solution). The resulting mixture was then stirred atroom temperature for four hours. A 5% sodium sulfite solution was thenadded to the reaction, along with 25 mL of diethyl ether. Followingseparation of the organic and aqueous layers, the organic layer waswashed sequentially with saturated aqueous sodium bicarbonate, thenbrine, dried (MgSO₄) and concentrated. Purification of the residue bycolumn chromatography on silica gel (5% methanol in dichloromethane)afforded the desired diol (418 mg, 51%).

[0560] To a cooled (0° C.) solution of N-Boc-3,4-pyrrolidinediol (2.53g, 12.5 mmol) in dichloromethane (80 mL) was added triethylamine (7 mL,50 mmol), and methanesulfonyl chloride (2.9 mL, 37.5 mmol). The mixturewas then stirred, gradually warming to room temperature, for 90 minutes.The mixture was then washed with saturated ammonium chloride and brine,dried and concentrated to afford the crude mesylate as a whitecrystalline solid (2.93 g, 68%). ¹H NMR (CDCl₃) δ 1.47 (s, 9H), 3.14 (brs, 3H), 3.66 (m, 2H), 3.77 (m, 2H), 5.16 (m, 2H). This material was usedwithout further purification in the next step.

[0561] To a solution of the mesylate (345 mg, 1.0 mmol) in DMF (8 mL)was added sodium azide (163 mg, 2.5 mmol). The mixture was then heatedto 120° C. for 4 hours. After cooling the reaction to room temperature,ethyl acetate (50 mL) was added, and the organic layer was extractedrepeatedly with water. The organic phase was dried and concentrated andthe residue was treated with trifluoroacetic acid (2 mL) indichloromethane (2 mL) for 2 hours at room temperature. The solventswere then removed under vacuum to afford 3,4-diazidopyrrolidine in a 71%yield (for 2-steps) as the TFA salt. ¹H NMR (CDCl₃) δ 3.14 (dd, 2H,J=13.1, 6.2 Hz), 3.55 (dd, 2H, J=13.1, 6.6 Hz), 3.64 (br s, 1H), 4.27(m, 2H).

[0562] To a solution ofN-[1-methylene-4-(chloromethylene)phenylene]-N-(2-nitrobenzenesulfonyl)-2-(aminomethyl)pyridine(692 mg, 2.0 mmol) in acetonitrile (20 mL) was added potassium carbonate(550 mg, 4.0 mmol) and the diazide.TFA salt (2 mmol) from above. Theresulting suspension was heated to 60° C. overnight. After cooling toroom temperature, water and ethylacetate were added to the reaction. Theorganic and aqueous layers were separated, and the aqueous layer wasextracted twice with ethylacetate. The combined organic layers weredried and concentrated and the residue was purified by columnchromatography on silica gel (5% methanol in dichloromethane) affordedthe desired product (697 mg, 48%). ¹H NMR (CDCl₃) δ 1.41 (br m, 9H),2.56 (d, 2H, J=12.2 Hz), 2.90 (d, 2H, J=12.2 Hz), 3.60 (s, 2H), 3.99 (s,2H), 4.43 (br s, 2H), 4.52 (br s, 2H), 7.15 (m, 2H), 7.21 (s, 4H), 7.61(t, 1H, J=7.5 Hz), 8.50 (d, 1H, J=4.1 Hz).

[0563]1-[[4-[[(N-t-buytoxycarbonyl)(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diaminopyrrolidine.

[0564] To a solution of the intermediate diazide from above (138 mg,0.298 mmol) in methanol (10 mL) was added Lindlar's catalyst (5% Pd onCaCO₃, 30 mg). The suspension was placed under 1 atm of hydrogen gas,and vigorously stirred for 3 hours. The mixture was then filteredthrough celite, and the filtrate was concentrated to give thecorresponding diamine in quantitative yield (122 mg). ¹H NMR (CDCl₃) δ1.41 (br m, 9H), 2.30 (dd, 2H, J=9.6, 6.2 Hz), 3.03 (dd, 2H, J=9.6,6.8), 3.56 (d, 2H, J=6.5 Hz), 3.63 (s, 2H), 4.43 (br s, 2H), 4.52 (br s,2H), 7.27 (m, 2H), 7.35 (s, 4H), 7.83 (ddd, 1H, J=8.4, 8.1, 0.9 Hz),8.50 (d, 1H, J=4.2 Hz).

[0565] Using general procedure D: Conversion of the amine (48 mg, 0.106mmol) to the hydrobromide salt with simultaneous deprotection of the BOCgroup afforded AMD7428 (61 mg). ¹H NMR (D₂O) δ 3.72 (dd, 2H, J=13.2, 6.6Hz), 4.00 (dd, 2H, J=13.2, 5.7 Hz), 4.39 (s, 2H), 4.41 (m, 2H), 4.58 (s,2H), 4.65 (s, 2H), 7.51 (br s, 4H), 7.99 (ddd, 1H, J=8.4, 8.1, 0.9 Hz),8.11 (dd, 1H, J=8.1, 1.5 Hz), 8.54 (ddd, 1H, J=8.4, 5.7, 1.5 Hz), 8.73(dd, 1H, J=5.7, 1.0 Hz). ¹³C NMR (D₂O) δ 48.96, 49.52, 51.40, 54.86,59.56, 127.07, 127.12, 131.57, 131.80, 132.79, 144.37, 146.42, 147.38,150.96. ES-MS m/z 312 (M+H). Anal. Calcd. for C₁₈H₂₅N₅.5.2HBr.3.0H₂O: C,27.50; H, 4.64; N, 8.91; Br, 52.85. Found: C, 27.49; H, 4.30; N, 8.70;Br, 52.84.

Example 206 AND7485: Preparation of1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diacetylaminopyrrolidine(hydrobromide salt)

[0566] To a solution of1-[[4-[[(N-t-buytloxycarbonyl)(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diaminopyrrolidine(60 mg, 0.146 mmol) in tetrahydrofuran (3 mL) was added4-dimethylaminopyridine (5 mg, 0.044 mmol), triethylamine (0.13 mL,0.949 mmol) and acetic anhydride (0.07 mL, 0.73 mmol). The reaction wasthen stirred at room temperature for 5 hours. After addition of water (5mL) and ethylacetate (25 mL), the aqueous and organic layers wereseparated. The aqueous layer was extracted twice with ethylacetate, andthe combined organic fractions were dried and concentrated. Purificationof the residue by column chromatography on silica gel (10% methanol indichloromethane) afforded the corresponding diamide (52 mg, 60%).

[0567] Using general procedure D: the diamide was converted to thehydrobromide salt with simultaneous deprotection of the BOC group togive AMD7485 (69 mg). ¹H NMR (D₂O) δ 2.00 (s, 6H), 3.53 (br s, 2H), 3.78(br s, 4H), 4.50 (s, 2H), 4.55 (s, 2H), 4.67 (s, 2H), 7.63 (s, 4H), 7.96(m, 2H), 8.46 (dd, 1H, J=8.4, 5.3 Hz), 8.83 (d, 1H, J=5.3 Hz). ¹³C NMR(D₂O) δ 22.28, 47.57, 54.32, 128.46, 128.84, 131.63, 131.71, 131.85,142.56, 144.09, 145.32, 147.95, 174.98. ES-MS m/z 396 (M+H). Anal.Calcd. for C₁₈H₂₅N₅.4.0HBr.3.0H₂O.0.6HOAc: C, 34.08; H, 5.23; N, 8.54;Br, 39.53. Found: C, 34.46; H, 5.09; N, 8.66; Br, 39.41.

Example 207 AMD8665: Preparation of8-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-2,5,8-triaza-3-oxabicyclo[4.3.0]nonane(hydrobromide salt)

[0568] To a solution of1-[[4-[[(N-t-buytloxycarbonyl)(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diaminopyrrolidine.(411 mg, 1.0 mmol) in THF (15 mL) was added di-tert-butyldicarbonate(218 mg, 1.0 mmol). The reaction was stirred at room temperature for 1hour. Ethylacetate (30 mL) was then added, and the mixture was extractedwith 10% citric acid (10 mL). Following drying and concentration of theorganic fractions, the residue was purified by column chromatography onsilica gel (5% methanol in dichloromethane) to give the desired product(one primary amine protected) (315 mg, 62%).

[0569] The intermediate from above was dissolved in THF (12 mL) to whichpotassium carbonate (170 mg, 1.24 mmol) was added. The mixture was thencooled to 0° C., and a solution of bromoacetyl bromide in THF (1 mL of a1M solution) was added in a dropwise manner over 10 minutes. Followingaddition, the reaction was stirred at 0° C. for one hour. The reactionwas then quenched with water and extracted with ethylacetate. Thecombined organic fractions were then dried and concentrated.

[0570] The residue was then treated with 2 mL of trifluoroacetic acid in2 mL of dichloromethane for one hour at room temperature. Followingremoval of the solvent and excess acid by vacuum, the crude reactionproduct was dissolved in acetonitrile (15 mL) to which potassiumcarbonate (250 mg, excess) was added. The mixture was stirred at roomtemperature for two hours. Filtration of the mixture and concentrationafforded a yellow residue, which was purified by column chromatographyon silica gel (2% aqueous ammonium hydroxide, 8% methanol, 90%chloroform) to yield the desired cyclic amide (115 mg, 43%).

[0571] Using general procedure D: the cyclic amide (88 mg, 0.250 mmol)was converted to a hydrobromide salt giving AMD8665 (68 mg). ¹H NMR(D₂O) δ 3.69 (dd, 1H, 12.9, 6.1 Hz), 3.86 (dd, 1H, J=12.6, 2.1 Hz),3.99-4.07 (br m, 4H), 4.10 (m, 2H), 4.50 (s, 2H), 4.63 (s, 2H), 4.74 (s,2H), 7.90 (br s, 4H), 7.94 (t, 1H, J=5.7 Hz), 7.99 (d, J=8.1 Hz), 8.43(t, 1H, J=8.1 Hz), 8.80 (d, 1H, J=5.7 Hz). ¹³C NMR (D₂O) δ 41.81, 48.68,49.68, 50.93, 51.41, 52.55, 57.81, 59.14, 127.31, 127.43, 130.98,131.55, 132.12, 132.84, 145.02, 145.95, 147.00, 166.28. ES-MS m/z 352(M+H). Anal. Calcd. for C₂₀H₂₅N₅O.3.9HBr.3.1H₂O: C, 33.23; H, 4.89; N,9.69; Br, 43.11. Found: C, 33.28; H, 4.72; N, 9.31; Br, 43.05.

Example 208 AMD8773: Preparation of8-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-2,5,8-triazabicyclo[4.3.0]nonane(hydrobromide salt)

[0572] The freebase of AMD8665 from above (18 mg, 0.05 mmol) wasdissolved in THF (3 mL). To this mixture, a solution of borane in THF(0.5 mL of a 1M solution) was added. The reaction was then heated to 60°C. for three hours. After cooling to room temperature, 2 mL of methanolwas carefully added to the reaction. The mixture was then concentratedunder vacuum, and the residue was re-dissolved in 3 mL ofethylenediamine. The reaction was then heated to 75° C. for three hours.After cooling to room temperature, 5 mL of water was added, the aqueouslayer was saturated with potassium carbonate, and then extractedrepeatedly with dichloromethane. The combined organic fractions werethen dried and concentrated to yield a pale yellow oil, which waspurified by column chromatograpy on silica gel (5% aqueous ammoniumhydroxide, 15% methanol, 80% dichloromethane) to afford the desiredproduct (11 mg, 64%).

[0573] Using general procedure D: the intermediate from above (22 mg,0.065 mmol) was converted to a hydrobromide salt giving AMD8773 (17 mg).¹H NMR (D₂O) δ 3.16 (m, 4H), 3.67 (m, 4H), 4.08 (br s, 2H), 4.41 (s,2H), 4.47 (s, 2H), 4.54 (s, 2H), 7.57 (s, 4H), 7.79 (dd, J=8.4, 5.3 Hz),8.11 (m, 1H), 8.67 (d, 1H, J=5.8 Hz). ¹³C NMR (D₂O) δ 39.45, 49.62,51.07, 51.86, 54.16, 59.43, 126.23, 131.32, 131.73, 131.89, 132,61,133.38, 146.53, 147.41, 151.22. ES-MS m/z 338 (M+H). Anal. Calcd. forC₂₀H₂₇N₅.4.8HBr.3.3H₂O: C, 30.59; H, 4.93; N, 8.92; Br, 48.84. Found: C,30.56; H, 4.83; N, 8.56; Br, 49.13.

1. A method to treat a disease mediated by a chemokine receptor in ahuman or animal subject, comprising administering to a subject in needof such treatment a compound of the formula

or a pharmaceutical composition thereof; wherein, W is a nitrogen atomand Y is void or, W is a carbon atom and Y=H; R¹ to R⁷ may be the sameor different and are independently selected from hydrogen or straight,branched or cyclic C₁₋₆ alkyl, where R¹ and R² together may form ═O; R⁸is a substituted heterocyclic group or a substituted aromatic group Aris an aromatic or heteroaromatic ring each optionally substituted atsingle or multiple, non-linking positions with electron-donating orwithdrawing groups; n and n′ are independently, 0-2; X is a group of theformula:

wherein, Ring A is an optionally substituted, saturated or unsaturated 5or 6-membered ring, and P is an optionally substituted carbon atom, anoptionally substituted nitrogen atom, sulfur or oxygen atom; whereinRing B is an optionally substituted 5 to 7-membered ring; wherein Ring Aor Ring B are bound to group W from any position through group V;wherein V is a chemical bond or V is a (CH₂)_(n″) group, (where n″=0-2)or V is a C═O group; and wherein Z is selected from the group consistingof: a hydrogen atom; an optionally substituted C₁₋₆ alkyl group; a C₀₋₆alkyl group substituted with an optionally substituted aromatic orheterocyclic group; an optionally substituted C₀₋₆ alkylamino or C₃₋₇cycloalkylamino group; and an optionally substituted carbonyl group orsulfonyl; and wherein further comprising any pharmaceutically acceptableacid addition salts thereof and any stereoisomeric forms and mixtures ofstereoisomeric forms thereof.
 2. The method of claim 1, wherein saiddisease involves angiogenesis or tumorigenesis.
 3. The method of claim2, wherein said tumorigenesis comprises tumors of: brain; breast;prostate; lung and haematopoetic tissues.
 4. The method of claim 1,wherein said disease is selected from the group consisting of: asthma,allergic rhinitis, hypersensitivity lung diseases, hypersensitivitypneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity,interstitial lung disease (ILD), idiopathic pulmonary fibrosis, ILDassociated with rheumatoid arthritis, systemic lupus erythematosus,ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome,polymyositis or dermatomyositis); systemic anaphylaxis orhypersensitivity responses, drug allergies, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,systemic lupus erythematosus, myastenia gravis, juvenile onset diabetes;glomerulonephritis, autoimmune throiditis, graft rejection, includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria;vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinphilic myotis, and eosiniphilic fasciitis.
 5. The method of claim1, wherein said disease is selected from the group consisting of:immunosuppression, including immunosuppression induced by chemotherapy,radiation therapy; disease relating to wound healing and burn treatment;therapy for autoimmune disease or other drug therapy (e.g.,corticosteroid therapy) or combination of conventional drugs used in thetreatment of autoimmune diseases and graft/transplantation rejection,which causes immunosuppression; immunosuppresion due to congenitaldeficiency in receptor function or other causes; and infectiousdiseases, such as parasitic diseases, including but not limited tohelminth infections, such as nematodes (round worms); Trichuriasis,Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis,filariasis; trematodes; visceral worms, visceral larva migtrans (e.g.,Toxocara), eosinophilic gastroenteritis (e.g., Anisaki spp., Phocanemassp.), cutaneous larva migrans (Ancylostona braziliense, Ancylostomacaninum); the malaria-causing protozoan Plasmodium vivax, Humancytomegalovirus, Herpesvirus saimiri, and Kaposi's sarcoma herpesvirus,also known as human herpesvirus 8, and poxvirus Moluscum contagiosum. 6.A method to affect the binding of a chemokine receptor selected from thegroup consisting of: CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CXCR-3, andCXCR-4, comprising administering to a mammalian subject an effectiveamount of a compound of the formula I in claim 1 or a pharmaceuticalcomposition thereof.
 7. A method to treat or prevent HIV in a subjectwhich method comprises administering to a subject in need of suchtreatment an effective amount of a compound of formula I in claim 1 or apharmaceutical composition thereof.
 8. The method of claim 7 whichfurther comprises administering one or more agents useful in theprevention or treatment of HIV.
 9. The method of claim 8, wherein saidone or more agents are selected from the group consisting of: nucleotidereverse transcriptase inhibitor such as zidovudine, didanosine,lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovirdipivoxil, fozivudine todoxil; non-nucleotide reverse transcriptaseinhibitor (including an agent having anti-oxidation activity such asimmunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz,loviride, immunocal, oltipraz, etc.; and protease inhibitors such assaquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir,lasinavir.
 10. The method of claim 1, wherein said optionallysubstituted 5 or 6-membered Ring A is selected from the group consistingof: benzene; pyridine; pyrimidine; pyrazine; pyridazine; triazine;piperidine; piperazine; imidazole; pyrazole; triazole; oxazole; andthiazole, or wherein said optionally substituted Ring B is selected fromthe group consisting of: benzene; 5 to 7-membered cycloalkyl ring;furan; dihydrofuran; tetrahydrofuran; thiophene; dihydrothiophene;tetrahydrothiophene (thiolane); pyran; dihydropyran; tetrahydropyran;thiapyran; dihydrothiapyran; tetrahydrothiapyran (pentamethylenesulfide); oxepine; and thiepin.
 11. The method of claim 10, wherein saidRing B comprises a 5 to 7-membered cycloalkyl ring selected from thegroup consisting of: cyclopentyl; cyclohexyl; cycloheptyl;cyclopentenyl; cyclohexenyl; and cycloheptenyl.
 12. The method of claim1, wherein said Ring B comprises a saturated heterocycloalkane.
 13. Themethod of claim 1, wherein said Ring A and said Ring B are each6-membered rings, independently selected from the group consisting of:dihydronaphthalene; tetrahydronaphthalene; dihydroquinoline andtetrahydroquinoline.
 14. The method of claim 1 wherein the compound offormula I is selected from the group consisting of: AMD7490,N-(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7491,N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7492,N-(2-pyridinylmethyl)-N′-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1,4-benzenedimethanamine;AMD8766,N-(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine;AMD8789,N-(2-pyridinylmethyl)-N′-(1-naphthalenyl)-1,4-benzenedimethanamine;AMD8776,N-(2-pyridinylmethyl)-N′-(8-quinolinyl)-1,4-benzenedimethanamine;AMD8859,N-(2-pyridinylmethyl)-N′-[2-[(2-pyridinylmethyl)amino]ethyl]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8867,N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-ylmethyl)amino]ethyl]-N′-(1-methyl-1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8746,N-(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8835,N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-ylmethyl)amino]ethyl]-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine;AMD8833,N-(2-pyridinylmethyl)-N′-(2-phenyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8825,N,N′-bis(2-pyridinylmethyl)-N′-(2-phenyl-5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8869,N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-5-quinolinyl)-1,4-benzenedimethanamine;AMD8876,N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-5-quinolinyl)-1,4-benzenedimethanamine;AMD8751,N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8777,N-(2-pyridinylmethyl)-N′-[(2-amino-3-phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8763,N-(2-pyridinylmethyl)-N′-(1H-imidazol-4-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8771,N-(2-pyridinylmethyl)-N′-(2-quinolinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8778,N-(2-pyridinylmethyl)-N′-(2-(2-naphthoyl)aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8781,N-(2-pyridinylmethyl)-N′-[(S)-(2-acetylamino-3-phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8782,N-(2-pyridinylmethyl)-N′-[(S)-(2-acetylamino-3-phenyl)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8788,N-(2-pyridinylmethyl)-N′-[3-((2-naphthalenylmethyl)amino)propyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8733 and AMD8734,N-(2-pyridinylmethyl)-N′-[2-(S)-pyrollidinylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8756,N-(2-pyridinylmethyl)-N′-[2-(R)-pyrollidinylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8799,N-(2-pyridinylmethyl)-N′-[3-pyrazolylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8728,N-(2-pyridinylmethyl)-N′-[2-pyrrolylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8836,N-(2-pyridinylmethyl)-N′-[2-thiopheneylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineAMD8841,N-(2-pyridinylmethyl)-N′-[2-thiazolylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8821,N-(2-pyridinylmethyl)-N′-[2-furanylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8742,N-(2-pyridinylmethyl)-N′-[2-[(phenylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8743,N-(2-pyridinylmethyl)-N′-(2-aminoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8753,N-(2-pyridinylmethyl)-N′-3-pyrrolidinyl-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamineAMD8754,N-(2-pyridinylmethyl)-N′-4-piperidinyl-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8784,N-(2-pyridinylmethyl)-N′-[2-[(phenyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8759,N-(2-pyridinylmethyl)-N′-(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;AMD8762,N-(2-pyridinylmethyl)-N′-(6-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;AMD8770,N-(2-pyridinylmethyl)-N′-(1-methyl-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;AMD8790,N-(2-pyridinylmethyl)-N′-(7-methoxy-3,4-dihydronaphthalenyl)-1-(aminomethyl)-4-benzamide;AMD8 805,N-(2-pyridinylmethyl)-N′-(6-methoxy-3,4-dihydronaphthalenyl)-1-(aminomethyl)-4-benzamide;AMD8902,N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;AMD8863,N-(2-pyridinylmethyl)-N′-(8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;AMD8886,N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(8-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;AMD8889,N-(2-pyridinylmethyl)-N′-(8-Fluoro-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;AMD8895,N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(8-Fluoro-1,2,3,4-tetrahydro-2-naphthalenyl)-1,4-benzenedimethanamine;AMD8852,N-(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine;AMD8858,N-(2-pyridinylmethyl)-N′-(1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-7-quinolinyl)-1,4-benzenedimethanamine;AMD8785,N-(2-pyridinylmethyl)-N′-[2-[(2-naphthalenylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8820,N-(2-pyridinylmethyl)-N′-[2-(isobutylamino)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8827, N-(2-pyridinylmethyl)-N′-[2-[(2-pyridinylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8828,N-(2-pyridinylmethyl)-N′-[2-[(2-furanylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8772,N-(2-pyridinylmethyl)-N′-(2-guanidinoethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;and AMD8861,N-(2-pyridinylmethyl)-N′-[2-[bis-[(2-methoxy)phenylmethyl]amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8862,N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-4-ylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8887,N-(2-pyridinylmethyl)-N′-[2-[(1H-imidazol-2-ylmethyl)amino]ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8816,N-(2-pyridinylmethyl)-N′-[2-(phenylureido)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8737,N-(2-pyridinylmethyl)-N′-[[N″-(n-butyl)carboxamido]methyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8739,N-(2-pyridinylmethyl)-N′-(carboxamidomethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8752,N-(2-pyridinylmethyl)-N′-[(N″-phenyl)carboxamidomethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8765,N-(2-pyridinylmethyl)-N′-(carboxymethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8715,N-(2-pyridinylmethyl)-N′-(phenylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8907,N-(2-pyridinylmethyl)-N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8927,N-(2-pyridinylmethyl)-N′-(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine(hydrobromide salt); AMD8926,N-(2-pyridinylmethyl)-N′-(5-nitro-1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8929,N-(2-pyridinylmethyl)-N′-[(1H)-5-azabenzimidazol-2-ylmethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD893 1,N-(2-pyridinylmethyl)-N-(4-phenyl-1H-imidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8783,N-(2-pyridinylmethyl)-N′-[2-(2-pyridinyl)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8764,N-(2-pyridinylmethyl)-N′-(2-benzoxazolyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8780,N-(2-pyridinylmethyl)-N′-(trans-2-aminocyclohexyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8818,N-(2-pyridinylmethyl)-N′-(2-phenylethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8829,N-(2-pyridinylmethyl)-N′-(3-phenylpropyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8839,N-(2-pyridinylmethyl)-N′-(trans-2-aminocyclopentyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8726,N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-glycinamide;AMD8738,N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-alaninamide;AMD8749,N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-aspartamide;AMD8750,N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-pyrazinamide;AMD8740,N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-prolinamide;AMD8741,N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-(L)-lysinamide;AMD8724,N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-benzamide;AMD8725,N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-picolinamide;AMD8713, N′-Benzyl-N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-urea;AMD8712, N′-phenyl-N-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-N-(5,6,7,8-tetrahydro-8-quinolinyl)-urea;AMD8716,N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-4-[[(2-pyridinylmethyl)amino]methyl]benzamide;AMD8717,N-(5,6,7,8-tetrahydro-8-quinolinyl)-4-[[(2-pyridinylmethyl)amino]methyl]benzamide;AMD8634,N,N′-bis(2-pyridinylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8774,N,N′-bis(2-pyridinylmethyl)-N′-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD8775,N,N′-bis(2-pyridinylmethyl)-N′-(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)-1,4-benzenedimethanamine;AMD8819,N,N′-bis(2-pyridinylmethyl)-N′-(1,2,3,4-tetrahydro-1-naphthalenyl)-1,4-benzenedimethanamine;AMD8768,N,N′-bis(2-pyridinylmethyl)-N′-[(5,6,7,8-tetrahydro-8-quinolinyl)methyl]-1,4-benzenedimethanamine;AMD8767,N,N′-bis(2-pyridinylmethyl)-N′[(6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)methyl]-1,4-benzenedimethanamine;AMD8838,N-(2-pyridinylmethyl)-N-(2-methoxyethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8871,N-(2-pyridinylmethyl)-N-[2-(4-methoxyphenyl)ethyl]-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD8844,N,N′-bis(2-pyridinylmethyl)-1,4-(5,6,7,8-tetrahydro-8-quinolinyl)benzenedimethanamine;AMD7129,N-[(2,3-dimethoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7130,N,N′-bis(2-pyridinylmethyl)-N-[1-(N″-phenyl-N″-methylureido)-4-piperidinyl]-1,3-benzenedimethanamine;AMD7131,N,N′-bis(2-pyridinylmethyl)-N-[N″-p-toluenesulfonylphenylalanyl)-4-piperidinyl]-1,3-benzenedimethanamine;AMD7136,N,N′-bis(2-pyridinylmethyl)-N-[1-[3-(2-chlorophenyl)-5-methyl-isoxazol-4-oyl]-4-piperidinyl]-1,3-benzenedimethanamine;AMD7138,N-[(2-hydroxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7140,N-[(4-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7141,N-[(4-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7142,N-[(4-acetamidophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7145,N-[(4-phenoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7147,N-[(1-methyl-2-carboxamido)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7151,N-[(4-benzyloxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;and AMD7155,N-[(thiophene-2-yl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine.AMD7156,N-[1-(benzyl)-3-pyrrolidinyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7159,N-[[1-methyl-3-(pyrazol-3-yl)]propyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7160,N-[1-(phenyl)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7164,N-[(3,4-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7166,N-[1-benzyl-3-carboxymethyl-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7167,N-[(3,4-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7168,N-(3-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7169,N-[[1-methyl-2-(2-tolyl)carboxamido]ethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7171,N-[(1,5-dimethyl-2-phenyl-3-pyrazolinone-4-yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7172,N-[(4-propoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7175,N-(1-phenyl-3,5-dimethylpyrazolin-4-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7177,N-[1H-imidazol-4-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7180,N-[(3-methoxy-4,5-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7182,N-[(3-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7184,N-[(3-cyanophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7185,N-(5-ethylthiophene-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7186,N-(5-ethylthiophene-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7187,N-[(2,6-difluorophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7188,N-[(2,6-difluorophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7189,N-[(2-difluoromethoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7195,N-(2-difluoromethoxyphenylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7196,N-(1,4-benzodioxan-6-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7197,N,N′-bis(2-pyridinylmethyl)-N-[1-(N″-phenyl-N″-methylureido)-4-piperidinyl]-1,4-benzenedimethanamine;AMD7198,N,N′-bis(2-pyridinylmethyl)-N-[N″-p-toluenesulfonylphenylalanyl)-4-piperidinyl]-1,4-benzenedimethanamine;AMD7199,N-[1-(3-pyridinecarboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7200,N-[1-(cyclopropylcarboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7201,N-[1-(1-phenylcyclopropylcarboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7202,N-(1,4-benzodioxan-6-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7203,N-[1-[3-(2-chlorophenyl)-5-methyl-isoxazol-4-carboxamido]-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7204,N-[1-(2-thiomethylpyridine-3-carboxamido)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7207,N-[(2,4-difluorophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7208,N-(1-methylpyrrol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7209,N-[(2-hydroxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7212,N-[(3-methoxy-4,5-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7216,N-(3-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7217,N-[2-(N″-morpholinomethyl)-1-cyclopentyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7220,N-[(1-methyl-3-piperidinyl)propyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7222,N-(1-methylbenzimidazol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7223,N-[1-(benzyl)-3-pyrrolidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7228,N-[[(1-phenyl-3-(N″-morpholino)]propyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7229,N-[1-(iso-propyl)-4-piperidinyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7230,N-[1-(ethoxycarbonyl)-4-piperidinyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD723 1,N-[(1-methyl-3-pyrazolyl)propyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7235,N-[1-methyl-2-(N″,N″-diethylcarboxamido)ethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7236,N-[(1-methyl-2-phenylsulfonyl)ethyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7238,N-[(2-chloro-4,5-methylenedioxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7239,N-[1-methyl-2-[N″-(4-chlorophenyl)carboxamido]ethyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7241,N-(1-acetoxyindol-3-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7242,N-[(3-benzyloxy-4-methoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7244,N-(3-quinolylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7245,N-[(8-hydroxy)-2-quinolylmethyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;and AMD7247,N-(2-quinolylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7249,N-[(4-acetamidophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7250,N-[1H-imidazol-2-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7251,N-(3-quinolylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7252,N-(2-thiazolylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7253,N-(4-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7254,N-[(5-benzyloxy)benzo[b]pyrrol-3-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7256,N-(l-methylpyrazol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7257,N-[(4-methyl)-1H-imidazol-5-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7259,N-[[(4-dimethylamino)-1-napthalenyl]methyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7260,N-[1,5-dimethyl-2-phenyl-3-pyrazolinone-4-ylmethyl]-N,N′-bis(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7261,N-[1-[(1-acetyl-2-(R)-prolinyl]-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7262,N-[1-[2-acetamidobenzoyl-4-piperidinyl]-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7270,N-[(2-cyano-2-phenyl)ethyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7272,N-[(N″-acetyltryptophanyl)-4-piperidinyl]-N-,[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7273,N-[(N″-benzoylvalinyl)-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7274,N-[(4-dimethylaminophenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7275,N-(4-pyridinylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD7276,N-(1-methylbenzimadazol-2-ylmethyl)-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,4-benzenedimethanamine;AMD7277,N-[1-butyl-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7278,N-[1-benzoyl-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7290,N-[1-(benzyl)-3-pyrrolidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7309,N-[(1-methyl)benzo[b]pyrrol-3-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7311,N-[1H-imidazol-4-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,3-benzenedimethanamine;AMD7359,N-[1-(benzyl)-4-piperidinyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7374,N-[1-methylbenzimidazol-2-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD7379,N-[(2-phenyl)benzo[b]pyrrol-3-ylmethyl]-N-[2-(2-pyridinyl)ethyl]-N′-(2-pyridinylmethyl)-1,4-benzenedimethanamine;AMD9025,N-[(6-methylpyridin-2-yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine;AMD9031,N-(3-methyl-1H-pyrazol-5-ylmethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;AMD9032,N-[(2-methoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;AMD9039,N-[(2-ethoxyphenyl)methyl]-N′-(2-pyridinylmethyl)-N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)-1,3-benzenedimethanamine;AMD9045,N-(benzyloxyethyl)-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;AMD9052,N-[(2-ethoxy-1-naphthalenyl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;and AMD9053,N-[(6-methylpyridin-2-yl)methyl]-N′-(2-pyridinylmethyl)-N-(5,6,7,8-tetrahydro-8-quinolinyl)-1,3-benzenedimethanamine;AMD7074,1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]guanidine;AMD7076, N-(2-pyridinylmethyl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1,4-benzenedimethanamine; AMD7078,1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]homopiperazine;AMD7079,1-[[3-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]homopiperazine;AMD7103 and 7104, trans andcis-1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,5-piperidinediamine;AMD3597,N,N′-[1,4-Phenylenebis(methylene)]bis-4-(2-pyrimidyl)piperazine;AMD3602,1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-1-(2-pyridinyl)methylamine;AMD3667,2-(2-pyridinyl)-5-[[(2-pyridinylmethyl)amino]methyl]-1,2,3,4-tetrahydroisoquinoline;AMD7428,1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diaminopyrrolidine;AMD7485,1-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-3,4-diacetylaminopyrrolidine;AMD8665,8-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-2,5,8-triaza-3-oxabicyclo[4.3.0]nonane;and AMD8773,8-[[4-[[(2-pyridinylmethyl)amino]methyl]phenyl]methyl]-2,5,8-triazabicyclo[4.3.0]nonane.